Gamma-aminoamide modulators of chemokine receptor activity

ABSTRACT

The present invention is directed to compounds of the formula (1), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 , R 12 , W, X, and n are defined herein, which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2.

BACKGROUND OF THE INVENTION

The chemokines are a family of small (70-120 amino acids),proinflammatory cytokines, with potent chemotactic activities.Chemokines are chemotactic cytokines that are released by a wide varietyof cells to attract various cells, such as monocytes, macrophages, Tcells, eosinophils, basophils and neutrophils to sites of inflammation(reviewed in Schall, Cytokine, 3, 165-183 (1991) and Murphy, Rev.Immun., 12, 593-633 (1994)). These molecules were originally defined byfour conserved cysteines and divided into two subfamilies based on thearrangement of the first cysteine pair. In the CXC-chemokine family,which includes IL-8, GROα, NAP-2 and IP-10, these two cysteines areseparated by a single amino acid, while in the CC-chemokine family,which includes RANTES, MCP-1, MCP-2, MCP-3, MIP-1α, MIP-1β and eotaxin,these two residues are adjacent.

The chemokines are secreted by a wide variety of cell types and bind tospecific G-protein coupled receptors (GPCRs) (reviewed in Horuk, TrendsPharm. Sci., 15, 159-165 (1994)) present on leukocytes and other cells.These chemokine receptors form a sub-family of GPCRs, which, at present,consists of fifteen characterized members and a number of orphans.Unlike receptors for promiscuous chemoattractants such as C5a, fMLP,PAF, and LTB4, chemkine receptors are more selectively expressed onsubsets of leukocytes. Thus, generation of specific chemokines providesa mechanism for recruitment of particular leukocyte subsets.

On binding their cognate ligands, chemokine receptors transduce anintracellular signal though the associated trimeric G protein, resultingin a rapid increase in intracellular calcium concentration. There are atleast seven human chemokine receptors that bind or respond toβ-chemokines with the following characteristic pattern: CCR-1 (or“CKR-1” or “CC-CKR-1”) [MIP-1α, MIP-1β, MCP-3, RANTES] (Ben-Barruch, etal., J. Biol. Chem., 270, 22123-22128 (1995); Beote, et al, Cell, 72,415-425 (1993)); CCR-2A and CCR-2B (or “CKR-2A”/“CKR-2A” or“CC-CKR-2A”/“CC-CKR-2A”) [MCP-1, MCP-2, MCP-3, MCP-4]; CCR-3 (or “CKR-3”or “CC-CKR-3”) [Eotaxin, Eotaxin 2, RANTES, MCP-2, MCP-3] (Rollins, etal., Blood, 90, 908-928 (1997)); CCR-4 (or “CKR-4” or “CC-CKR-4”)[MIP-1α, RANTES, MCP-1] (Rollins, et al., Blood 90, 908-928 (1997));CCR-5 (or “CKR-5” or “CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson, etal., Biochemistry, 35, 3362-3367 (1996)); and the Duffy blood-groupantigen [RANTES, MCP-1] (Chaudhun, et al., J. Biol. Chem., 269,7835-7838 (1994)). The β-chemokines include eotaxin, MIP (“macrophageinflammatory protein”), MCP (“monocyte chemoattractant protein”) andRANTES (“regulation-upon-activation, normal T expressed and secreted”)among other chemokines.

Chemokine receptors, such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4,CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediatorsof inflammatory and immunoregulatory disorders and diseases, includingasthma, rhinitis and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Humans whoare homozygous for the 32-basepair deletion in the CCR-5 gene appear tohave less susceptibility to rheumatoid arthritis (Gomez, et al.,Arthritis & Rheumatism, 42, 989-992 (1999)). A review of the role ofeosinophils in allergic inflammation is provided by Kita, H., et al., J.Exp. Med. 183, 2421-2426 (1996). A general review of the role ofchemokines in allergic inflammation is provided by Lustger, A. D., NewEngland J. Med., 338(7), 426-445 (1998). A subset of chemokines arepotent chemoattractants for monocytes and macrophages. The bestcharacterized of these is MCP-1 (monocyte chemoattractant protein-1),whose primary receptor is CCR2. MCP-1 is produced in a variety of celltypes in response to inflammatory stimuli in various species, includingrodents and humans, and stimulates chemotaxis in monocytes and a subsetof lymphocytes. In particular, MCP-1 production correlates with monocyteand macrophage infiltration at inflammatory sites. Deletion of eitherMCP-1 or CCR2 by homologous recombination in mice results in markedattenuation of monocyte recruitment in response to thioglycollateinjection and Listeria monocytogenes infection (Lu et al., J. Exp. Med.,187, 601-608 (1998); Kurihara et al. J. Exp. Med., 186, 1757-1762(1997); Boring et al. J. Clin. Invest., 100, 2552-2561 (1997); Kuziel etal. Proc. Natl. Acad. Sci., 94, 12053-12058 (1997)). Furthermore, theseanimals show reduced monocyte infiltration into granulomatous lesionsinduced by the injection of schistosomal or mycobacterial antigens(Boring et al. J. Clin. Invest., 100, 2552-2561 (1997); Warmington etal. Am J. Path., 154, 1407-1416 (1999)). These data suggest thatMCP-1-induced CCR2 activation plays a major role in monocyte recruitmentto inflammatory sites, and that antagonism of this activity will producea sufficient suppression of the immune response to produce therapeuticbenefits in immunoinflammatory and autoimmune diseases. Accordingly,agents which modulate chemokine receptors such as the CCR-2 receptorwould be useful in such disorders and diseases. In addition, therecruitment of monocytes to inflammatory lesions in the vascular wall isa major component of the pathogenesis of atherogenic plaque formation.MCP-1 is produced and secreted by endothelial cells and intimal smoothmuscle cells after injury to the vascular wall in hypercholesterolemicconditions. Monocytes recruited to the site of injury infiltrate thevascular wall and differentiate to foam cells in response to thereleased MCP-1. Several groups have now demonstrated that aortic lesionsize, macrophage content and necrosis are attenuated in MCP-1 −/−or CCR2−/− mice backcrossed to APO-E −/−, LDL-R −/− or Apo B transgenic micemaintained on high fat diets (Boring et al. Nature, 394, 894-897 (1998);Gosling et al. J. Clin. Invest., 103, 773-778 (1999)). Thus, CCR2antagonists may inhibit atherosclerotic lesion formation andpathological progression by impairing monocyte recruitment anddifferentiation in the arterial wall.

SUMMARY OF THE INVENTION

The present invention is further directed to compounds which aremodulators of chemokine receptor activity and are useful in theprevention or treatment of certain inflammatory and immunoregulatorydisorders and diseases, allergic diseases, atopic conditions includingallergic rhinitis, dermatitis, conjunctivitis, and asthma, as well asautoimmune pathologies such as rheumatoid arthritis and atherosclerosis.The invention is also directed to pharmaceutical compositions comprisingthese compounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which chemokine receptorsare involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   W is selected from the group consisting of:    -   C, N, and —O—, wherein when W is N, then R⁴ is absent, and when        W is —O—, then both R³ and R⁴ are absent;-   X is selected from the group consisting of:    -   —NR¹⁰—, —O—, —CH₂O—, —CONR¹⁰—, —NR¹⁰CO—, —CO₂—, —OCO—,        —CH₂(NR¹⁰)CO—, —N(COR¹⁰)—, and —CH₂N(COR¹⁰)—,        and where R¹⁰ is independently selected from: hydrogen, C₁₋₆        alkyl, benzyl, phenyl,    -   and C₁₋₆ alkyl-C₃₋₆ cycloalkyl,    -   which is unsubstituted or substituted with 1-3 substituents        where the substituents are independently selected from: halo,        C₁₋₃alkyl,    -   C₁₋₃alkoxy and trifluoromethyl;        or where R¹⁰ and R² may be joined together to form a 5- or        6-membered ring,-   R¹ is selected from:    -   hydrogen, —C₀₋₆alkyl-Y-phenyl-, —CO₀alkyl-Y-heterocycle-,        —C₀₋₆alkyl-Y—(C₁₋₆alkyl)-, and    -   —(C₀₋₆alkyl)-Y—(C₀₋₆alkyl)-(C₃₋₇cycloalkyl)-(C₀₋₆alkyl),        -   where Y is selected from:        -   a single bond, —O—, —S—, —SO—, —SO₂—, and —NR¹⁰—,        -   and where the phenyl, heterocycle, alkyl and the cycloalkyl            are unsubstituted or substituted with 1-7 substituents where            the substituents are independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₃alkyl,        -   (d) trifluoromethyl,        -   (e) C₁₋₃alkyl,        -   (f) —C₃₋₆cycloalkyl        -   (g) —CO₂R⁹, wherein R⁹ is independently selected from:            hydrogen, C₁₋₆ alkyl, C₅₋₆ cycloalkyl, benzyl or phenyl,            which is unsubstituted or substituted with 1-3 substituents            where the substituents are independently selected from:            halo, C₁₋₃alkyl, C₁₋₃alkoxy and trifluoromethyl,        -   (h) —CN,        -   (i) —NR⁹R¹⁰,        -   (j) —NR⁹COR¹⁰,        -   (k) —NR⁹SO₂R¹⁰,        -   (l) —NR⁹CO₂R¹⁰,        -   (m) —NR⁹CONR⁹R¹⁰,        -   (n) —CONR⁹R¹⁰,        -   (o) heterocycle,        -   (p) phenyl;-   R² is selected from:    -   (C₀₋₆alkyl)-phenyl and (C₀₋₆alkyl)-heterocycle,        -   where the alkyl is unsubstituted or substituted with 1-7            substituents where the substituents are independently            selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₃alkyl,        -   (d) trifluoromethyl,        -   (e) —C₁₋₃alkyl,        -   (f) —CO₂R⁹, and        -   (g) oxo;            and where the phenyl and the heterocycle may be            unsubstituted or substituted with 1-5 substituents where the            substituents are independently selected from:    -   (a) halo,    -   (b) trifluoromethyl,    -   (c) trifluoromethoxy,    -   (d) hydroxy,    -   (e) C₁₋₆alkyl,    -   (f) C₃₋₇cycloalkyl,    -   (g) —O—C₁₋₆alkyl,    -   (h) —O—C₃₋₇cycloalkyl,    -   (i) —SCF₃,    -   (j) —S—C₁₋₆alkyl,    -   (k) —SO₂—C₁₋₆alkyl,    -   (l) phenyl,    -   (m) heterocycle,    -   (n) —CO₂R⁹,    -   (O)—CN,    -   (p) —NR⁹R¹⁰,    -   (q) —NR⁹—SO₂—R¹⁰,    -   (r) —SO₂—NR⁹R¹⁰,    -   (s) —CONR⁹R¹⁰, and    -   (t) —O-phenyl;-   R³ is selected from:    -   hydrogen, (C₀₋₆alkyl)-phenyl, (C₀₋₆alkyl)-heterocycle,        C₁₋₆alkyl, CF₃, C₃₋₇cycloalkyl, —NR⁹R¹⁰, —CO₂R⁹, —NR⁹—SO₂—R¹⁰,        —NR⁹CONR⁹R¹⁰, and —CONR⁹R⁰,        -   where the alkyl is unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₃alkyl, and        -   (d) trifluoromethyl,            and where the phenyl, heterocycle, and cycloalkyl are            unsubstituted or substituted with 1-5 substituents where the            substituents are independently selected from:    -   (a) halo,    -   (b) trifluoromethyl,    -   (c) hydroxy,    -   (d) C₁₋₃alkyl,    -   (e) —O—C₁₋₃alkyl,    -   (f) —CO₂R⁹,    -   (g) —CN,    -   (h) —NR⁹R¹⁰, and    -   (i) —CONR⁹R¹⁰    -   (j) NR⁹SO₂R¹⁰,    -   (k) SO₂NR⁹R¹⁰    -   (l) phenyl,    -   (m) heterocycle;        and where the phenyl, heterocycle, and cycloalkyl may or may not        be fused to another phenyl or heterocycle;-   R⁴ is selected from:    -   (a) hydrogen,    -   (b) hydroxy,    -   (c) C₁₋₆alkyl,    -   (d) C₁₋₆alkyl-hydroxy,    -   (e) —O—C₁₋₁₃alkyl,    -   (f) C₀₋₆CO₂R⁹,    -   (g) —CONR⁹R¹⁰, and    -   (h) —CN;        or R³ and R⁴ may be joined together to form a ring which is        selected from:    -   (a) 1H-indene,    -   (b) 2,3-dihydro-1H-indene,    -   (c) 2,3-dihydro-benzofuran,    -   (d) 1,3-dihydro-isobenzofuran,    -   (e) 2,3-dihydro-benzothiofuran, and    -   (f) 1,3-dihydro-isobenzothiofuran,    -   where the 1H-indene, 2,3-dihydro-1H-indene,        2,3-dihydro-benzofuran, 1,3-dihydro-isobenzofuran,        2,3-dihydrobenzothiofuran, and 1,3-dihydro-isobenzothiofuran may        be unsubstituted or substituted with 1-5 substituents where the        substituents are independently selected from:        -   (i) halo,        -   (ii) trifluoromethyl,        -   (iii) hydroxy,        -   (iv) C₁₋₃alkyl,        -   (v) —O—C₁₋₃alkyl,        -   (vi) C₀₋₄CO₂R⁹,        -   (vii) —CN,        -   (viii) —NR⁹R¹⁰, and        -   (ix) —CONR⁹R¹⁰        -   (x) NR⁹SO₂R¹⁰,        -   (xi) SO₂NR⁹R¹⁰        -   (xii) phenyl,        -   (xiii) heterocycle;            R⁵, R⁶, R⁷ and R⁸ are independently selected from:    -   (a) hydrogen,    -   (b) hydroxy,    -   (c) C₁₋₆alkyl,    -   (d) C₁₋₆alkyl-hydroxy,    -   (e) —O—C₁₋₃alkyl,    -   (f) oxo, and    -   (g) halo,    -   (h) C₀₋₄CO₂R⁹, and    -   (i) CF₃,    -   or where R⁵ and R⁶, or R⁷ and R⁸ may be joined together via a        C₂₋₃alkyl chain to form a ring, or where R³ and R⁵, or R⁴ and R⁶        may be joined together to form a ring which is phenyl,        heterocycle, or cycloalkyl, wherein the ring is unsubstituted or        substituted with 1-7 substituents where the substituents are        independently selected from:        -   (i) halo,        -   (ii) trifluoromethyl,        -   (iii) hydroxy,        -   (iv) C₁₋₃alkyl,        -   (V) —O—C₁₋₃alkyl,        -   (vi) —CO₂R⁹,        -   (vii) —CN,        -   (viii) —NR⁹R¹⁰,        -   (ix) —CONR⁹R¹⁰, and        -   (x) phenyl;-   R¹¹ is selected from:    -   (a) hydrogen,    -   (b) halo    -   (c) C₁₋₆alkyl,    -   (d) hydroxy,    -   (e) CO₂R⁹,    -   (f) —O—C₁₋₃alkyl, and    -   (g) —NR⁹R¹⁰;-   R¹² is selected from:    -   (a) hydrogen,    -   (b) C₁₋₆alkyl, and    -   (c) CO₂R⁹;-   n is an integer selected from 0, 1, 2 and 3;    and pharmaceutically acceptable salts thereof and individual    diastereomers thereof.

More preferred compounds of the present invention include those offormula Ib:

wherein the dashed line represents a single or a double bond and R¹, R²,and R⁵ are defined herein, and wherein R¹⁵ and R¹⁶ are independentlyselected from:

-   -   (a) hydrogen,    -   (b) halo,    -   (c) trifluoromethyl,    -   (d) hydroxy,    -   (e) C₁₋₃alkyl,    -   (f) —O—C₁₋₃alkyl,    -   (g) —CO₂H,    -   (h) —CO₂C₁₋₃alkyl,    -   (i) —CN, and    -   (j) heterocycle;        and pharmaceutically acceptable salts and individual        diastereomers thereof.

More preferred compounds of the present invention also include those offormula Ic:

wherein R¹, R², R⁵, R¹⁵, and R¹⁶ are defined herein.

More preferred compounds of the present invention include those offormula Id:

wherein R¹, R², and R⁵ are defined herein, andwhere Z is a heterocycle selected from the group consisting of:benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl,indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl,pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof,and where the heterocycle may be unsubstituted or substituted with 1-3substituents, where the substituents are selected from:

-   -   (a) hydrogen,    -   (b) halo,    -   (c) trifluoromethyl,    -   (d) hydroxy,    -   (e) C₁₋₃alkyl,    -   (f) —O—C₁₋₃alkyl,    -   (g) —CO₂H,    -   (h) —CO₂C₁₋₁₃alkyl, and    -   (i) —CN,    -   and where the heterocycle may be fused to a phenyl or another        heterocycle, and pharmaceutically acceptable salts and        individual diastereomers thereof.

In the present invention it is preferred that X is —CONH—.

In the present invention it is preferred that R¹ is selected from:

-   -   —C₀₋₆alkyl-phenyl, C₀₋₆alkyl-heterocycle, —C₁₋₆alkyl,        —C₀₋₆alkyl-O—C₁₋₆alkyl-, —C₀₋₆alkyl-S—C₁₋₆alkyl-, and        —(C₀₋₆alkyl)-(C₃₋₇cycloalkyl)-(C₀₋₆alkyl),        -   where the phenyl, heterocycle, alkyl and the cycloalkyl are            unsubstituted or substituted with 1-7 substituents where the            substituents are independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₃alkyl,        -   (d) trifluoromethyl,        -   (e) C₁₋₃alkyl,        -   (f) —C₃₋₆cycloalkyl        -   (g) —CO₂R⁹, wherein R⁹ is independently selected from:            hydrogen, C₁₋₆ alkyl, C₅₋₆ cycloalkyl, benzyl or phenyl,            which is unsubstituted or substituted with 1-3 substituents            where the substituents are independently selected from:            halo, C₁₋₃alkyl, C₁₋₃alkoxy and trifluoromethyl,        -   (h) —CN,        -   (i) —NR⁹R¹⁰,        -   (j) —NR⁹COR¹⁰,        -   (k) —NR⁹SO₂R¹⁰,        -   (l) —NR⁹CO₂R¹⁰,        -   (m) —NR⁹CONR⁹R¹⁰,        -   (n) —CONR⁹R¹⁰,        -   (o) heterocycle, and        -   (p) phenyl.

In the present invention it is more preferred that R¹ is selected from:

-   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6    substituents where the substituents are independently selected from:    -   (a) halo,    -   (b) hydroxy,    -   (c) —O—C₁₋₃alkyl,    -   (d) trifluoromethyl,    -   (e) —CN,    -   (f) —NR⁹SO₂R¹⁰,    -   (g) —NR⁹CO₂R¹⁰,    -   (h) —NR⁹CONR⁹R¹⁰,    -   (i) heterocycle,    -   (j) —CO₂R⁹, and    -   (k) —CONR⁹R¹⁰,-   (2) —C₀₋₆alkyl-O—C₁₋₆alkyl-, which is unsubstituted or substituted    with 1-6 substituents where the substituents are independently    selected from:    -   (a) halo, and    -   (b) trifluoromethyl,-   (3) —C₀₋₆alkyl-S—C₁₋₆alkyl-, which is unsubstituted or substituted    with 1-6 substituents where the substituents are independently    selected from:    -   (a) halo, and    -   (b) trifluoromethyl,-   (4) —(C₃₋₅cycloalkyl)-(C₀₋₆alkyl), which is unsubstituted or    substituted with 1-7 substituents where the substituents are    independently selected from:    -   (a) halo,    -   (b) hydroxy,    -   (c) —O—C₁₋₃alkyl,    -   (d) trifluoromethyl,    -   (e) —CN,    -   (f) —NR⁹SO₂R¹⁰,    -   (g) —NR⁹CO₂R¹⁰,    -   (h) —NR⁹CONR⁹R¹⁰,    -   (i) heterocycle,    -   (j)—CO₂R⁹, and    -   k) —CONR⁹R¹⁰,-   (5) phenyl, which is unsubstituted or substituted with 1-5    substituents where the substituents are independently selected from:    -   (a) halo,    -   (b) hydroxy,    -   (c) —O—C₁₋₃alkyl,    -   (d) trifluoromethyl,    -   (e) —CN,    -   (f) —NR⁹SO₂R¹⁰,    -   (g) —NR⁹CO₂R¹⁰,    -   (h) —NR⁹CONR⁹R¹⁰,    -   (i) heterocycle,    -   (j) —CO₂R⁹, and    -   (k) —CONR⁹R¹⁰,    -   or where the phenyl may be fused to another phenyl or        heterocycle,-   (6) heterocycle, which is unsubstituted or substituted with 1-5    substituents where the substituents are independently selected from:    -   (a) halo,    -   (b) hydroxy,    -   (c) —O—C₁₋₃alkyl,    -   (d) trifluoromethyl,    -   (e) —CN,    -   (f) —NR⁹SO₂R¹⁰,    -   (g) —NR⁹CO₂R¹⁰,    -   (h) —NR⁹CONR⁹R¹⁰,    -   (i) heterocycle,    -   (O)—CO₂R⁹, and    -   (k) —CONR⁹R¹⁰,    -   or where the heterocycle is fused to another heterocycle or a        phenyl.

In the present invention it is even more preferred that R¹ is selectedfrom:

-   -   and positional and stereo isomers thereof.

In the present invention it is preferred that R² is selected from:—(C₀₋₄alkyl)-phenyl and —(C₀₋₄alkyl)-heterocycle, where heterocycle isselected from:

-   -   furanyl, imidazolyl, oxadiazolyl, oxazolyl, pyrazolyl,        pyrazinyl, pyridyl, pyridazinyl, pyrimidyl, pyrrolyl,        thiadiazolyl, thiazolyl, thienyl, and triazolyl, and N-oxides        thereof,        where the alkyl is unsubstituted or substituted with 1-7        substituents where the substituents are independently selected        from:    -   (a) halo,    -   (b) hydroxy,    -   (c) —O—C₁₋₃alkyl,    -   (d) trifluoromethyl,    -   (e) —CO₂R⁹        and where the phenyl or heterocycle is unsubstituted or        substituted with 1-5 substituents where the substituents are        independently selected from:    -   (a) halo,    -   (b) trifluoromethyl,    -   (c) trifluoromethoxy,    -   (d) hydroxy,    -   (e) C₁₋₃alkyl,    -   (f) —O—C₁₋₃alkyl,    -   (g) —CO₂R⁹,    -   (h) —S—C₁₋₃alkyl,    -   (i) —SO₂—C₁₋₃alkyl,    -   (j) —SCF₃,    -   (k) —OPh,    -   (l) —NR⁹R¹⁰,    -   (m) —NR⁹—SO₂—R¹⁰,    -   (n) —SO₂—NR⁹R¹⁰,    -   (o)—CONR⁹R¹⁰, and    -   (p) heterocycle.

In the present invention it is more preferred that R² is selected from:

-   -   —CH₂-phenyl and —CH₂-heterocycle, where the heterocycle is        selected from: pyridyl, pyridazinyl, pyrimidyl, and N-oxides        thereof,    -   and where the phenyl or heterocycle is unsubstituted or        substituted with 1-3 substituents where the substituents are        independently selected from:        -   (a) halo,        -   (b) trifluoromethyl,        -   (c) trifluoromethoxy,        -   (d) hydroxy,        -   (e) C₁₋₃alkyl,        -   (f) —O—C₁₋₃alkyl,        -   (g) —CO₂—C₃alkyl,        -   (h) —CO₂H,        -   (i) —S—C₁₋₃alkyl,        -   (j) —SO₂—C₁₋₃alkyl,        -   (k) —SCF₃,        -   (l) —NH₂,        -   (m) —NH—SO₂—C₁₋₃alkyl,        -   (n) —SO₂—NH₂, and        -   (o) heterocycle.

In the present invention it is still more preferred that R² is selectedfrom:

-   (1) —CH₂-(phenyl),-   (2) —CH₂-(4-bromophenyl),-   (3) —CH₂-(3-chlorophenyl),-   (4) —CH₂-(3,5-difluorophenyl),-   (5) —CH₂-((2-trifluoromethyl)phenyl),-   (6) —CH₂-((3-trifluoromethyl)phenyl),-   (7) —CH₂-((4-trifluoromethyl)phenyl),-   (8) —CH₂-((3-trifluoromethoxy)phenyl),-   (9) —CH₂-((3-trifluoromethylthio)phenyl),-   (10) —CH₂-((3-trifluoromethoxy-5-thiomethyl)phenyl),-   (11) —CH₂-((3-trifluoromethoxy-5-methoxy)phenyl),-   (12) —CH₂-((3-trifluoromethoxy-5-methanesulfonyl)phenyl),-   (13) —CH₂-((3-trifluoromethoxy-5-amino)phenyl),-   (14) —CH₂-((3-trifluoromethoxy-5-aminomethanesulfonyl)phenyl),-   (15) —CH₂-((3-trifluoromethoxy-5-sulfonylamino)phenyl),-   (16) —CH₂-((3,5-bis-trifluoromethyl)phenyl),-   (17) —CH₂-((3-fluoro-5-trifluoromethyl)phenyl),-   (18) —CH(CH₃)-((3,5-bis-trifluoromethyl)phenyl),-   (19) —C(CH₃)₂-((3,5-bis-trifluoromethyl)phenyl),-   (20) —CH₂-(4-(2-trifluoromethyl)pyridyl),-   (21) —CH₂-(5-(3-trifluoromethyl)pyridyl),-   (22) —CH₂-(5-(3-trifluoromethyl)pyridazinyl),-   (23) —CH₂-(4-(2-trifluoromethyl)pyridyl-N-oxide), and-   (24) —CH₂-(5-(3-trifluoromethyl)pyridyl-N-oxide).

In the present invention it is preferred that R³ is phenyl orheterocycle, where the phenyl or heterocycle is unsubstituted orsubstituted with 1-5 substituents

-   -   where the substituents are independently selected from:    -   (a) halo,    -   (b) trifluoromethyl,    -   (c) hydroxy,    -   (d) C₁₋₃alkyl,    -   (e) —O—C₁₋₃alkyl,    -   (f) —CO₂R⁹,    -   (g) —CN,    -   (h) —NR⁹R¹⁰, and    -   (i) —CONR⁹R¹⁰.

In the present invention it is more preferred that R³ is phenyl orheterocycle, where the phenyl or heterocycle is unsubstituted orsubstituted with 1-3 substituents where the substituents areindependently selected from:

-   -   (a) halo,    -   (c) hydroxy,    -   (d) C₁₋₃alkyl,    -   (e) —O—C₁₋₃alkyl, and    -   (f) —CO₂R⁹.

In the present invention it is still more preferred that R³ is phenyl,para-fluorophenyl, 3-carboxyphenyl, 3-pyridyl, 3,5-pyrimidyl,1-benzimidazole, 3-indole, 1-indazole, 1-pyrrole, imidazoyl, diazoyl,triazoyl or tetrazoyl.

In the present invention it is more preferred that R⁴ is selected from:

-   -   (a) hydrogen,    -   (b) hydroxy,    -   (c) —CO₂C₁₋₆alkyl,    -   (d) —CN,    -   (e) fluoro, and    -   (f) methyl.

In the present invention it is more preferred that R⁵ and R⁶ areindependently selected from:

-   -   (a) hydrogen,    -   (b) hydroxy,    -   (c) —CH₃,    -   (d) —O—CH₃,    -   (e) oxo, and    -   (f)-fluoro.

In the present invention it is preferred that R¹¹ is hydrogen.

In the present invention it is preferred that R¹² is hydrogen.

Especially preferred compounds of the present invention include those ofthe formula:

wherein the dashed line represents a single or a double bond, R⁵ ishydrogen or methyl, and R¹ and R² are defined herein;and pharmaceutically acceptable salts and individual diastereomersthereof.

Especially preferred compounds of the present invention include those ofthe formula:

wherein R¹ and R² are defined herein;and pharmaceutically acceptable salts and individual diastereomersthereof.

Especially preferred compounds of the present invention include those ofthe formula:

wherein R¹ and R² are defined herein;and pharmaceutically acceptable salts and individual diastereomersthereof. Representative compounds of the present invention include thosepresented in the Examples and pharmaceutically acceptable salts andindividual diastereomers thereof.

The compounds of the instant invention have at least one asymmetriccenter at the position α-to the amide carbonyl. Additional asymmetriccenters may be present depending upon the nature of the varioussubstituents on the molecule. Each such asymmetric center willindependently produce two optical isomers and it is intended that all ofthe possible optical isomers and diastereomers in mixtures and as pureor partially purified compounds are included within the ambit of thisinvention. The absolute configurations of the more preferred compoundsof this invention are of the configuration shown below, where theposition α-to the amide carbonyl

is designated as being of the “S” absolute configuration (when R¹¹ is H,although the designation at this position may be specified as “R” if thepriority for assignment of the groups at that position differs).

The absolute configurations of the more preferred compounds of thisinvention having the structure below are as shown, where the positionα-to the amide carbonyl

is designated as being of the “S” absolute configuration, and where thepiperidine 3 and 4 positions have the 3-(R) and 4-(R) configurations.

The independent syntheses of diastereomers and enantiomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

As appreciated by those of skill in the art, C₁₋₃alkyl is defined toidentify the group as having 1, 2 or 3 carbons in a linear or branchedarrangement, such that C₁₋₃alkyl specifically includes methyl, ethyl,n-propyl, and iso-propyl.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. As used herein,“pharmaceutically acceptable salts” refer to derivatives wherein theparent compound is modified by making acid or base salts thereof.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can beprepared from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred. Suitable salts are found, e.g. inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418.

Specific compounds within the present invention include a compound whichselected from the group consisting of: the title compounds of theExamples;

and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.

The subject compounds are useful in a method of modulating chemokinereceptor activity in a patient in need of such modulation comprising theadministration of an effective amount of the compound. The presentinvention is directed to the use of the foregoing compounds asmodulators of chemokine receptor activity. In particular, thesecompounds are useful as modulators of the chemokine receptors, inparticular CCR-2.

The utility of the compounds in accordance with the present invention asmodulators of chemokine receptor activity may be demonstrated bymethodology known in the art, such as the assay for chemokine binding asdisclosed by Van Riper, et al., J. Exp. Med., 177, 851-856 (1993) whichmay be readily adapted for measurement of CCR-2 binding.

Receptor affinity in a CCR-2 binding assay was determined by measuringinhibition of ¹²⁵I-MCP-1 to the endogenous CCR-2 receptor on variouscell types including monocytes, THP-1 cells, or after heterologousexpression of the cloned receptor in eukaryotic cells. The cells weresuspended in binding buffer (50 mM HEPES, pH 7.2, 5 mM MgCl₂, 1 mMCaCl₂, and 0.50% BSA) with and added to test compound or DMSO and¹²⁵I-MCP-1 at room temperature for 1 h to allow binding. The cells werethen collected on GFB filters, washed with 25 mM HEPES buffer containing500 mM NaCl and cell bound ¹²⁵I-MCP-1 was quantified.

In a chemotaxis assay chemotaxis was performed using T cell depletedPBMC isolated from venous whole or leukophoresed blood and purified byFicoll-Hypaque centrifugation followed by rosetting withneuramimidase-treated sheep erythrocytes. Once isolated, the cells werewashed with HBSS containing 0.1 mg/ml BSA and suspended at 1×10⁷cells/ml. Cells were fluorescently labeled in the dark with 2 μMCalcien-AM (Molecular Probes), for 30 min at 37° C. Labeled cells werewashed twice and suspended at 5×10⁶ cells/m in RPMI 1640 with glutamine(without phenol red) containing 0.1 mg/ml BSA. MCP-1 (Peprotech) at 10ng/ml diluted in same medium or medium alone were added to the bottomwells (27 μl). Monocytes (150,000 cells) were added to the topside ofthe filter (30 μl) following a 15 min preincubation with DMSO or withvarious concentrations of test compound. An equal concentration of testcompound or DMSO was added to the bottom well to prevent dilution bydiffusion. Following a 60 min incubation at 37° C., 5% CO₂, the filterwas removed and the topside was washed with HBSS containing 0.1 mg/mlBSA to remove cells that had not migrated into the filter. Spontaneousmigration (chemokinesis) was determined in the absence ofchemoattractant.

In particular, the compounds of the following examples had activity inbinding to the CCR-2 receptor in the aforementioned assays, generallywith an IC₅₀ of less than about 1 μM. Such a result is indicative of theintrinsic activity of the compounds in use as modulators of chemokinereceptor activity.

Mammalian chemokine receptors provide a target for interfering with orpromoting eosinophil and/or lymphocyte function in a mammal, such as ahuman. Compounds which inhibit or promote chemokine receptor function,are particularly useful for modulating eosinophil and/or lymphocytefunction for therapeutic purposes. Accordingly, compounds which inhibitor promote chemokine receptor function would be useful in treating,preventing, ameliorating, controlling or reducing the risk of a widevariety of inflammatory and immunoregulatory disorders and diseases,allergic diseases, atopic conditions including allergic rhinitis,dermatitis, conjunctivitis, and asthma, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Forexample, an instant compound which inhibits one or more functions of amammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation. As aresult, one or more inflammatory processes, such as leukocyteemigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) orinflammatory mediator release, is inhibited.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

Diseases and conditions associated with inflammation and infection canbe treated using the compounds of the present invention. In a preferredembodiment, the disease or condition is one in which the actions oflymphocytes are to be inhibited or promoted, in order to modulate theinflammatory response.

Diseases or conditions of humans or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, particularly bronchialasthma, allergic rhinitis, hypersensitivity lung diseases,hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler'ssyndrome, chronic eosinophilic pneumonia), delayed-typehypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis.

Diseases or conditions of humans or other species which can be treatedwith modulators of chemokine receptor function, include, but are notlimited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms), (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis),trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis), visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), and cutaneous larvamigraines (Ancylostona braziliense, Ancylostoma caninum). In addition,treatment of the aforementioned inflammatory, allergic and autoimmunediseases can also be contemplated for promoters of chemokine receptorfunction if one contemplates the delivery of sufficient compound tocause the loss of receptor expression on cells through the induction ofchemokine receptor internalization or delivery of compound in a mannerthat results in the misdirection of the migration of cells.

The compounds of the present invention are accordingly useful intreating, preventing, ameliorating, controlling or reducing the risk ofa wide variety of inflammatory and immunoregulatory disorders anddiseases, allergic conditions, atopic conditions, as well as autoimmunepathologies. In a specific embodiment, the present invention is directedto the use of the subject compounds for treating, preventing,ameliorating, controlling or reducing the risk of autoimmune diseases,such as rheumatoid arthritis or psoriatic arthritis.

In another aspect, the instant invention may be used to evaluateputative specific agonists or antagonists of chemokine receptors,including CCR-2. Accordingly, the present invention is directed to theuse of these compounds in the preparation and execution of screeningassays for compounds which modulate the activity of chemokine receptors.For example, the compounds of this invention are useful for isolatingreceptor mutants, which are excellent screening tools for more potentcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other compounds tochemokine receptors, e.g., by competitive inhibition. The compounds ofthe instant invention are also useful for the evaluation of putativespecific modulators of the chemokine receptors, including CCR-2. Asappreciated in the art, thorough evaluation of specific agonists andantagonists of the above chemokine receptors has been hampered by thelack of availability of non-peptidyl (metabolically resistant) compoundswith high binding affinity for these receptors. Thus the compounds ofthis invention are commercial products to be sold for these purposes.

The present invention is further directed to a method for themanufacture of a medicament for modulating chemokine receptor activityin humans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The present invention is further directed to the use of the presentcompounds in treating, preventing, ameliorating, controlling or reducingthe risk of infection by a retrovirus, in particular, herpes virus orthe human immunodeficiency virus (HIV) and the treatment of, anddelaying of the onset of consequent pathological conditions such asAIDS. Treating AIDS or preventing or treating infection by HIV isdefined as including, but not limited to, treating a wide range ofstates of HIV infection: AIDS, ARC (AIDS related complex), bothsymptomatic and asymptomatic, and actual or potential exposure to HIV.For example, the compounds of this invention are useful in treatinginfection by HIV after suspected past exposure to HIV by, e.g., bloodtransfusion, organ transplant, exchange of body fluids, bites,accidental needle stick, or exposure to patient blood during surgery.

In a preferred aspect of the present invention, a subject compound maybe used in a method of inhibiting the binding of a chemokine to achemokine receptor, such as CCR-2, of a target cell, which comprisescontacting the target cell with an amount of the compound which iseffective at inhibiting the binding of the chemokine to the chemokinereceptor.

The subject treated in the methods above is a mammal, preferably a humanbeing, male or female, in whom modulation of chemokine receptor activityis desired. “Modulation” as used herein is intended to encompassantagonism, agonism, partial antagonism, inverse agonism and/or partialagonism. In a preferred aspect of the present invention, modulationrefers to antagonism of chemokine receptor activity. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. The terms“administration of,” and or “administering a” compound should beunderstood to mean providing a compound of the invention to theindividual in need of treatment. As used herein, the term “treatment”refers both to the treatment and to the prevention or prophylactictherapy of the aforementioned conditions.

Combined therapy to modulate chemokine receptor activity for therebytreating, preventing, ameliorating, controlling or reducing the risk ofinflammatory and immunoregulatory disorders and diseases, includingasthma and allergic diseases, as well as autoimmune pathologies such asrheumatoid arthritis and atherosclerosis, and those pathologies notedabove is illustrated by the combination of the compounds of thisinvention and other compounds which are known for such utilities.

For example, in treating, preventing, ameliorating, controlling orreducing the risk of inflammation, the present compounds may be used inconjunction with an antiinflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, such as an inhibitor of5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor,an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide, a non-steroidal antiinflammatory agent, or acytokine-suppressing antiinflammatory agent, for example with a compoundsuch as acetaminophen, aspirin, codeine, embrel, fentanyl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, tenidap, and the like.Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine;an antiitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the treatment/prevention/suppressionor amelioration of the diseases or conditions for which compounds of thepressent invention are useful. Such other drugs may be administered, bya route and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

Examples of other active ingredients that may be combined with acompound of the present invention, either administered separately or inthe same pharmaceutical compositions, include, but are not limited to:(a) VLA-4 antagonists such as those described in U.S. Pat. No.5,510,332, WO95/15973, WO96/01644, WO96/06108, WO96/20216, WO96/22966,WO96/31206, WO96/40781, WO97/03094, WO97/02289, WO 98/42656, WO98/53814,WO98/53817, WO98/53818, WO98/54207, and WO98/58902; (b) steroids such asbeclomethasone, methylprednisolone, betamethasone, prednisone,dexamethasone, and hydrocortisone; (c) immunosuppressants such ascyclosporin, tacrolimus, rapamycin and other FK-506 typeimmunosuppressants; (d) antihistamines (H1-histamine antagonists) suchas bromopheniramine, chlorpheniramine, dexchlorpheniramine,triprolidine, clemastine, diphenhydramine, diphenylpyraline,tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine,azatadine, cyproheptadine, antazoline, pheniramine pyrilamine,astemizole, terfenadine, loratadine, desloratadine, cetirizine,fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as β2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (i) other antagonists of thechemokine receptors, especially CCR-1, CCR-2, CCR-3, CXCR-3 and CCR-5; () cholesterol lowering agents such as HMG-CoA reductase inhibitors(lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin,rosuvastatin, and other statins), sequestrants (cholestyramine andcolestipol), cholesterol absorption inhibitors (ezetimibe), nicotinicacid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrateand benzafibrate), and probucol; (k) anti-diabetic agents such asinsulin, sulfonylureas, biguanides (metformin), α-glucosidase inhibitors(acarbose) and glitazones (troglitazone and pioglitazone); (1)preparations of interferon beta (interferon beta-1α, interferonbeta-1β); (m) other compounds such as 5-aminosalicylic acid and prodrugsthereof, antimetabolites such as azathioprine and 6-mercaptopurine, andcytotoxic cancer chemotherapeutic agents.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith an NSAID the weight ratio of the compound of the present inventionto the NSAID will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of thepresent invention and other active ingredients will generally also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used. In such combinations the compoundof the present invention and other active agents may be administeredseparately or in conjunction. In addition, the administration of oneelement may be prior to, concurrent to, or subsequent to theadministration of other agent(s).

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin. Oily suspensions may be formulated bysuspending the active ingredient in a vegetable oil, for example arachisoil, olive oil, sesame oil or coconut oil, or in a mineral oil such asliquid paraffin. The oily suspensions may contain a thickening agent,for example beeswax, hard paraffin or cetyl alcohol. Sweetening agentssuch as those set forth above, and flavoring agents may be added toprovide a palatable oral preparation. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. The pharmaceutical compositions of theinvention may also be in the form of oil-in-water emulsions. The oilyphase may be a vegetable oil, for example olive oil or arachis oil, or amineral oil, for example liquid paraffin or mixtures of these. Suitableemulsifying agents may be naturally-occurring gums, for example gumacacia or gum tragacanth, naturally-occurring phosphatides, for examplesoy bean, lecithin, and esters or partial esters derived from fattyacids and hexitol anhydrides, for example sorbitan monooleate, andcondensation products of the said partial esters with ethylene oxide,for example polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents. Syrups and elixirs may beformulated with sweetening agents, for example glycerol, propyleneglycol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables. The compoundsof the present invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols. Fortopical use, creams, ointments, jellies, solutions or suspensions, etc.,containing the compounds of the present invention are employed. (Forpurposes of this application, topical application shall includemouthwashes and gargles.)

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of these pathologicalconditions. In treating, preventing, ameliorating, controlling orreducing the risk of conditions which require chemokine receptormodulation an appropriate dosage level will generally be about 0.01 to500 mg per kg patient body weight per day which can be administered insingle or multiple doses. Preferably, the dosage level will be about 0.1to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kgper day. A suitable dosage level may be about 0.01 to 250 mg/kg per day,about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day.Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50mg/kg per day. For oral administration, the compositions are preferablyprovided in the form of tablets containing 1.0 to 1000 milligrams of theactive ingredient, preferably 2.0 to 500, more preferably 3.0 to 200,particularly 1, 5, 10, 15, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200,250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made by known procedures or as illustrated.

The preparation of compounds within the scope of the instant inventionis detailed in Scheme 1, starting from commercially available or known1-1, where R¹⁷ is hydrogen or an alkyl protecting group (Greene, T;Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley &Sons, Inc., New York, N.Y. 1991). Formation of the dianion of carboxylicacid 1-1, where R¹⁷ is a hydrogen atom, with 2 equivalents of a basesuch as LDA or LHMDS, followed by treatment with allyl bromide gives1-2a (where R¹⁷ is H). Alternatively, an ester may be used as thestarting material 1-1 (where R¹⁷ can be methyl, ethyl, benzyl, ort-butyl). In this case deprotonation with one equivalent of base, suchas LDA, KHMDS, LHMDS, NaH, and the like, followed by treatment withallyl bromide furnishes 1-2 (where R¹⁷ is an alkyl group). Conversion ofester 1-2 to the carboxylic acid 1-2a can be achieved by a number ofconditions depending on the nature of the ester. For example, methyl orethyl esters can be readily saponified with sodium hydroxide, or lithiumhydroxide; tert-butyl ester can be removed by treatment with TFA.Coupling of the acid 1-2a with amine 1-3 to give amide 1-4 can beaccomplished by the standard amide bond formation conditions using acoupling reagent such as DCC, EDC and a catalyst such as DMAP, HOBT orHOAT. Oxidation of the olefin 1-4 to the aldehyde 1-5 can be carried outunder numerous conditions, such as with ozone followed by treatment withmethyl sulfide or triphenylphosphine, or with osmium tetroxide andsodium periodate (see March J. “Advanced Organic Chemistry”, 4th ed.,John Wiley & Sons, New York, pp. 1167-1171 (1992)). Reductive aminationwith amine 1-6 in the presence of a borohydride such as sodiumtriacetoxyborohydride or sodium cyanoborohydride then provides thecompound of formula I. Alternatively, compounds of formula I may beprepared in one pot by reductive amination of the ozonide withoutconverting it to the ketone. When R¹ is not hydrogen, a chiral center isgenerated by alkylation with allyl bromide. The resulting acid 1-2a canbe resolved in a variety of ways, including by crystallization withoptically pure amines such as α-methylbenzylamine. The resolved acid canthen be used to prepare I as a single enantiomer, or as a singlediastereomer when other chiral centers are present.

The preparation of aldehydes 1-5 as intermediates can also be achievedas depicted in Scheme 1A. Alkylation of 1-1 with commercially availablebromoacetaldehyde dimethyl acetal can be achieved with a strong basesuch as sodium, lithium or potassium hexamethyldisilazide, lithiumdiisopropylamide, and the like, to give 1-7. Conversion of ester 1-7 tothe carboxylic acid 1-7a can be achieved by a number of conditionsdepending on the nature of the ester. For example, methyl or ethylesters can be readily saponified with potassium hydroxide, sodiumhydroxide, or lithium hydroxide. Coupling of the acid 1-7a with amine1-3 to give amide 1-8 can be accomplished by the standard amide bondformation conditions using a coupling reagent such as DCC, EDC and acatalyst such as DMAP, HOBT or HOAT. These compounds can be thenconverted to the compound of formula I according to Scheme 1.

The preparation of carboxylic acids 1-2a as intermediates can also beachieved as depicted in Scheme 1B. Activation of acid 1-1a by formationof an acid chloride or mixed anhydride under standard conditions,followed by treatment with an optically pure lithium oxazolidinone 1-9(R can be isopropyl or benzyl; other related oxazolidinones may beused), furnishes the N-acyloxazolidinone 1-10, according to precedentsby Evans et al Evans, D. A., Ennis, M. D., Mathre, D. J., J. Am. Chem.Soc. 1982, 104, 1737). Deprotonation of 1-10 with one equivalent ofstrong base, such as LDA, ADS, LHMDS, and the like, followed bytreatment with allyl bromide furnishes 1-11 as a single isomer afterpurification, again according to the precedents of Evans et al.Conversion of N-acyloxazolidinone 1-11 to the optically pure carboxylicacid 1-2a can be achieved by a number of conditions including treatmentwith lithium hydroperoxide, or bases such as potassium hydroxide, sodiumhydroxide, or lithium hydroxide. Scalemic 1-2a can be then converted toisomerically pure compounds of formula I according to Scheme 1.

The preparation of carboxylic acids 1-7a as intermediates can also beachieved as depicted in Scheme 1C. Deprotonation of 1-10 (Scheme 1B)with one equivalent of strong base, such as LDA, KHMDS, LHMDS, and thelike, followed by treatment with bromoacetaldehyde dimethyl acetalfurnishes 1-12 as a single isomer after purification. Conversion ofN-acyloxazolidinone 1-12 to the optically pure carboxylic acid 1-7a canbe achieved by a number of conditions including treatment with lithiumhydroperoxide, or bases such as potassium hydroxide, sodium hydroxide,or lithium hydroxide. Scalemic 1-7a can be then converted toisomerically pure compounds of formula I according to Scheme 1.

Compounds within the scope of the instant invention can alternatively beprepared as detailed in Scheme 2, starting from 1-2 (see Scheme 1),where R¹⁷ is an alkyl protecting group such as methyl, ethyl, benzyl ort-butyl (Greene, T; Wuts, P. G. M. Protective Groups in: OrganicSynthesis, John Wiley & Sons, Inc., New York, N.Y. 1991). Oxidation ofthe olefin 1-2 to the aldehyde 2-1 can be carried out under numerousconditions, such as with ozone followed by treatment with methyl sulfideor triphenylphosphine, or with osmium tetroxide and sodium periodate(see March J. “Advanced Organic Chemistry”, 4th ed., John Wiley & Sons,New York, pp. 1167-1171 (1992)). Reductive amination with amine 1-6 inthe presence of a borohydride such as sodium triacetoxyborohydride orsodium cyanoborohydride then provides the compound 2-2. Hydrolysis of2-2 can be achieved by a number of conditions depending on the nature ofthe ester. For example, methyl or ethyl esters can be readily saponifiedwith sodium hydroxide, or lithium hydroxide; tert-butyl ester can beremoved by treatment with TFA. Coupling of the acid 2-2a with amine 1-3to give the compound of the formula I can be accomplished by thestandard amide bond formation conditions using a coupling reagent suchas DCC, EDC and a catalyst such as DMAP, HOBT or HOAT.

In certain cases, it may be necessary to protect R¹, for example in thecases of certain aminoheterocycles, in order to proceed with thesyntheses in Schemes 1 and 2. Scheme 3 shows one general exampleinvolving 1-1b, where R¹ is 4-(2-aminothiazole). Compound 1-1b iscommercially available, where R¹⁰ is ethyl. Protection of 1-1b with at-butoxycarbonyl group can be accomplished with BOC₂O to give 3-1b.Deprotonation with a strong base such as n-butyl lithium, followed bytreatment with allyl bromide provides 1-2b, which can be carried tocompounds of formula I in the usual way as described in Scheme 2. Theapproach shown in Scheme 2b can be applied to a variety of closelyrelated aminoheterocycles, for example 3-(5-aminoisothiazole) and5-(2-aminothiazole).

The preparation of esters 1-2 as intermediates can also be achieved asdepicted in Scheme 4. Commercially available acid 4-1 can be protectedas an ester by various means, depending upon the nature of R¹⁷ (i.e.,methyl, ethyl, benzyl, t-butyl). For example, the t-butyl ester can beprepared using t-butanol, magnesium sulfate, and sulfuric acid accordingto the method of Wright, et al (Wright, S. W., Hageman, D. L., Wright,A. S., McClure, L. D. Tetrahedron Lett. 1997, 38(42), 7345).Deprotonation of 4-2 with a strong base such as LDA, followed bytreatment with an electrophile such as an alkyl halide, a ketone, analdehyde, an epoxide, or an α, β-unsaturated ester, nitrile or nitrocompound can provide 1-2, which in turn may be used to prepare compoundsof the formula I as described in Schemes 1 and 2.

In an extension of the strategy shown in Scheme 4, compounds 1-2c can beprepared by alkylation of the enolate of 4-2 with γ-bromo-α,β-unsaturated ester or nitrile 4-3. The trans cyclopropanes are obtainedand the diastereoselectivity of this reaction to give erythro or threoproducts can be controlled by solvent choice according to the work ofPrempree, et al. (J. Org. Chem. 1983, 48, 3553, and Tetrahedron Lett.1985, 26, 1723). Compounds 1-2c may be used to prepare compounds of theformula I as described in Schemes 1 and 2.

Compounds 1-2 can be modified as shown in Scheme 4B so that R¹¹ issomething other than hydrogen, for example methyl, hydroxy, and fluoro.Treatment of 1-2 with a strong base such as t-butyl lithium, followed bymethyl iodide, gives 1-2d. Similarly, deprotonation of 1-2 with a strongbase such as potassium hexamethylsilazide, followed by treatment withcamphorsulfonyl oxaziridine or N-fluorobenzenesulfonamide provideshydroxy and fluoro compounds 1-2e and 1-2f, respectively. Intermediates1-2d, 1-2e, and 1-2f can be carried on to compounds of the formula I(except where the hydrogen α-to the amide carbonyl is replaced bymethyl, hydroxy and fluoro) using the methods outlined in Schemes 2.

Compounds within the scope of the instant invention can alternatively beprepared as detailed in Scheme 5, starting from 1-1 (see Scheme 1),where R¹⁷ is an alkyl protecting group such as t-butyl (Greene, T; Wuts,P. G. M. Protective Groups in Organic Synthesis, John Wiley & Sons,Inc., New York, N.Y. 1991). Deprotonation of 1-1 with one equivalent ofstrong base, such as LDA, KHMDS, LHMDS, and the like, followed bytreatment with bromides 5-1 (for example commercially available3-bromo-2-methylpropene) furnishes 5-2. Oxidation of the olefin 5-2 tothe ketone followed by reduction to the alcohol 5-3 can be carried outunder numerous conditions, such as with ozone followed by treatment withsodium borohydride, or with osmium tetroxide and sodium periodate (seeMarch J. “Advanced Organic Chemistry”, 4th ed., John Wiley & Sons, NewYork, pp. 1167-1171 (1992)), again followed by sodium borohydride.Mitsunobo reaction (Mitsunobu, O. Synthesis 1981, 1) of 5-3 withglutarimides 5-4 (glutarimide is commercially available, substitutedanalogs are known from the literature) gives intermediates 5-5.Reduction of the imide 5-5 can be accomplished with BH₃.DMS to provide5-6. Hydrolysis of the ester 5-6 can be achieved by a number ofconditions depending on the nature of the ester. For example, methyl orethyl esters can be readily saponified with sodium hydroxide, or lithiumhydroxide; tert-butyl ester can be removed by treatment with TFA.Coupling of the acid 5-6a with amine 1-3 to give the compound of theformula Ia can be accomplished by the standard amide bond formationconditions using a coupling reagent such as DCC, EDC and a catalyst suchas DMAP, HOBT or HOAT.

Compounds within the scope of the instant invention can alternatively beprepared as detailed in Scheme 6, starting from 1-2a (see Scheme 1).Reduction of the acid to the corresponding alcohol 6-1 can beaccomplished by forming the mixed anhydride with isobutylchloroformateand a base such as N-methylmorpholine, followed by reduction with NaBH₄.The intermediate 6-1 can be converted to ethers 6-2 in a variety ofways, for example, by treatment with NaH and an alkyl halide. Oxidationof the olefin 6-2 to the aldehyde 6-3 can be carried out under numerousconditions, such as with ozone followed by treatment with methyl sulfideor triphenylphosphine, or with osmium tetroxide and sodium periodate(see March J. “Advanced Organic Chemistry”, 4th ed., John Wiley & Sons,New York, pp. 1167-1171 (1992)). Reductive amination with amine 1-6 inthe presence of a borohydride such as sodium triacetoxyborohydride orsodium cyanoborohydride then provides the compound of formula Ib.

In some cases it is desirable to carry out late modifications ofcompounds I. For example, heterocycles can be modified in a variety ofways as shown in Scheme 7, 7A and 7B, as well as by other means.Compounds Id, prepared as described in Schemes 2 and 3, can bedeprotected with TFA to give compounds of the formula Ie. Coversion ofIe to the corresponding amides If, Ureas Ig, carbamates Ih, andguanidines Ii, can be accomplished using under a variety of conditions,including those outlined in Scheme 7.

As an extension to the examples in Scheme 7, one can construct a varietyof rings off of the aminothiazole core. Scheme 7a gives two examples.Compounds Id, prepared as described in Schemes 2 and 3, can be reactedwith Boc-ethanolamines (R²⁰═H, or alkyl groups) in the presence oftriphenylphosphine and diethylazodicarboxylate to give adducts 7-1.Deprotection with, for example, TFA gives diamines 7-2, which in turncan be cyclized in a number of different ways, including by treatmentwith phosgene in the presence of a base such as diisopropylethylamine toprovide compounds of the formula Ij. Related compounds of the formula Ikcan be prepared starting from compounds Ie. Amide coupling under avariety of conditions (such as with EDC and catalytic DMAP) affords 7-3.Rearrangement is accomplished by treatment with NaH and DMF to provide7-4. Cyclization can be achieved by standard amide coupling with, forexample, EDC and catalytic DMAP, to give the target compounds of theformula Ik.

Scheme 7b shows how the thiazole core may be linked to various aryl andheteroaryl groups. Intermediate 1-1b can be converted to thecorresponding 2-halothiazole 7-5 by, for example, treatment witht-butylONO and CuBr₂. Elaboration to compounds of the formula 7-6 isaccomplished using protocols described in Schemes 1 and 2. Compounds 7-6can readily be coupled to aryl and heteroarylboronic acids and stannanesunder palladium catalyzed conditions, to give compounds of the formulaII.

Substituted cyclopropyl compounds may be modified in a variety of waysas shown in part in Scheme 8. Compounds 1-2c (prepared as described inScheme 4A) can be elaborated to compounds 8-1 using the methods shown inSchemes 1 or 2. These, in turn can be hydrolyzed to the correspondingcarboxylic acids Im. The acids can be converted to carbamates by aCurtius rearrangement and then further converted to amines, amides,ureas, sulfonamides, heterocycles, etc., using standard techniques knownto those skilled in the art. Alternatively, the acids can be reduced tothe corresponding primary alcohols which, themselves may be carried onto amines, amides, carbamates, ureas, sulfonamides, and heterocycles,using standard techniques known to those skilled in the art.Additionally, the carboxylic acids and nitriles 8-1 can themselves beconverted to heterocycles. Substituted cyclopropyl compounds of theformulas 8-1, and Im-r have at least three stereocenters, allowing for 8possible isomers. These can be separated a various stages of thesyntheses by a number of means including, preparative thin layerchromatography, flash chromatography, HPLC, and HPLC using columns withchiral packing components.

The subject compounds may be prepared by modification of the proceduresdisclosed in the Examples as appropriate. Starting materials are made byknown procedures or as illustrated. The following examples are providedfor the purpose of further illustration only and are not intended to belimitations on the disclosed invention. The following are representativeprocedures for the preparation of the compounds used in the followingExamples or which can be substituted for the compounds used in thefollowing Examples which may not be commercially available.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided for the purpose of furtherillustration only and are not intended to be limitations on thedisclosed invention.

Concentration of solutions was generally carried out on a rotaryevaporator under reduced pressure. Flash chromatography was carried outon silica gel (230-400 mesh). NMR spectra were obtained in CDCl₃solution unless otherwise noted. Coupling constants (3) are in hertz(Hz). Abbreviations: diethyl ether (ether), triethylamine (TEA),N,N-diisopropylethylamine (DIEA) saturated aqueous (sat'd), roomtemperature (rt), hour(s) (h), minute(s) (min).

The following are representative Procedures for the preparation of thecompounds used in the following Examples or which can be substituted forthe compounds used in the following Examples which may not becommercially available.

Intermediate 1

Step A:

To a mechanically stirred solution of 4-fluorophenylacetic acid (50.0 g,0.324 mol) in 800 mL THF at about −15° C. (ice salt bath) was addeddropwise LHMDS in THF (1.0 M, 811 mL, 0.811 mol) over 2.25 h. Initiallyduring the addition, the mixture was a slurry, then at the end themixture cleared. After an additional 0.5 h, allyl bromide (30.9 mL, 43.2g, 0.357 mol) was added neat, dropwise over 3 minutes. The reactionmixture was stirred for 15 minutes, then warmed to rt, stirred another0.5 h and quenched by pouring into 1N HCl solution (1L). The resultingmixture was extracted three times with ethyl acetate (400 mL). Thecombined organic layers were washed with brine (800 mL), dried overanhydrous MgSO₄, filtered, and concentrated to afford 63 g of crudeproduct.

To the crude acid in ethyl acetate (˜1L) was added(S)-(−)-α-methylbenzylamine (23.6 g, 0.194 mol). The mixture was warmedto ˜60° C. until most of the solids had dissolved (more ethyl acetatewas added), then cooled to rt while stirring. The solids were collectedby filtration and recrystallized twice from hot ethyl acetate to give23.2 g of salt. The free acid was obtained by partitioning between 1NHCl and ethyl acetate. The organic phase was washed again with 1N HCl,then with brine, dried over anhydrous MgSO₄, and concentrated to give15.5 g of acid (49% yield) as a clear oil which solidified on standing.¹H NMR (CDCl₃, 400 MHz): δ 7.26 (m, 2H), 7.00 (m, 2H), 5.68 (m, 1H),4.98-5.08 (m, 2H), 3.61 (t, J=7.6 Hz, 1H), 2.78 (m, 1H), 2.49 (m, 1H).

The enantiomeric purity of the acid prepared above was determined byderivatization with L-Trp-OMe (amide formation). The methyl ester signalfor the resolved acid (one singlet, 3.59 ppm)) was compared with that ofthe racemic acid (two singlets, 3.59 and 3.66 ppm) and determined tobe >95% de, hence the acid is >95% ee. The procedure for derivatizationis as follows:

4-fluorophenylpentenoic acid (21 mg, 0.11 mmol), L-Trp-OMe.HCl (41 mg,0.16 mmol), EDC (31 mg, 0.16 mmol), HOBt (22 mg, 0.16 mmol), and DIEA(37 μL, 0.22 mmol) were combined in DCM and stirred overnight. Thereaction mixture was diluted with more DCM, and washed with water, thenbrine. The organic layer was dried over MgSO₄, filtered andconcentrated.Step B:

(S)-2-(4-fluorophenyl)-pentenoic acid (4.93 g, 25.4 mmol),3,5-Bis(trifluoromethyl) benzylamine (6.48 g, 26.7 mmol), EDC (5.85 g,30.5 mmol) and HOBt (4.12 g, 30.5 mmol) were combined in DCM and stirredovernight. The reaction mixture was diluted with more DCM and washedtwice with water and once with brine. The organic layer was dried overanhydrous MgSO₄, filtered, and concentrated. The crude product waspurified by flash chromatography (5% MeOH/DCM) to afford 9.41 g (88%) ofa white solid. H NMR (CDCl₃, 500 MHZ): δ 7.76 (s, 1H), 7.58 (s, 2H),7.28 (m, 2H), 7.05 (m, 2H), 5.96 (br s, 1H), 5.74 (m, 1H), 5.02-5.11 (m,2H), 4.53 (d, J=6 Hz, 2H), 3.49 (t, J=7.50 Hz, 1H), 2.92 (m, 1H), 2.52(m, 1H). ESI-MS calc. for C20H16F7NO: 419; Found: 420 (M+H).

Intermediate 2

Intermediate 1 (5.05 g, 12.0 mmol), prepared in step B above, wasdissolved in acetone (30 mL) and cooled to −78° C. 03 was bubbledthrough this solution for 15 min, at which point the solution hadchanged from colorless to blue. Nitrogen gas was passed through thesolution until the blue color had disappeared and then dimethylsulfide(8.84 mL, 7.48 g, 120 mmol) was added and the reaction mixture allowedto warm to rt. After 1 h at rt, the reaction mixture was concentratedand the crude product was used as is in subsequent reactions. TLC andHNMR indicated that the product was a mixture, probably the result ofintramolecular cyclization of the aldehyde and amide groups. Thepresence of aldehyde in the mixture was verified by HNMR which showed apeak at 9.81 ppm. This crude material was used as is in reductiveamination reactions.

Intermediate 3

4-(4-Fluorophenyl)piperidine hydrochloride is now commercially availablefrom Arch Corporation (catalog # AR01507). It can also be prepared inquantitative yield from commercially available4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (20 g. 94mmol) by hydrogenation using Pd/C catalyst (2 g) in 200 mL of ethanol at40 psi H₂ pressure for 2 days using a Parr aparatus.

Intermediate 4

Step A:

To a solution of thionyl chloride (6.58 mL, 10.7 g, 90.2 mmol) in CHCl₃(10 mL) was added dropwise commercially available1-(2-hydroxyethylamino)-2-propanol (5.0 g, 42 mmol) in CHCl₃ (5 mL). Theresulting reaction was exothermic. The reaction mixture was brought toreflux whereupon it became a thick slurry. An additional 5 mL of CHCl₃was added. The reaction mixture was stirred at reflux for 2.5 h, thenconcentrated under vacuum to afford 7.97 g (99%) of crude salt. ESI-MScalc. for C5H11Cl2N: 155; Found: 156 (M+H).Step B:

The hydrochloride salt prepared as described in Step A above (7.89 g,41.0 mmol) and Boc₂O (8.94 g, 41.0 mmol) were combined in DCM (75 mL).Triethylamine (8.6 mL, 6.2 g, 62 mmol) was then added and an ice waterbath was used to control the exotherm. The reaction was then allowed tostir at rt for 6 h. The mixture was then diluted with DCM and washedthree times with 1 N HCl, once with saturated NaHCO₃ solution, and oncewith brine. The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The resulting crude product was purified by MPLC,eluting with a 10-15% gradient of ethyl acetate/hexane, to give 4.45 g(42%) of pure product. H NMR (CDCl₃, 400 M): δ 4.30,4.17 (m, 1H,rotamers), 3.50-3.72 (m, 5H), 3.37 (dd, J=14.8, 7.6 Hz, 0.5 H, rotamer),3.21 (dd, J=14.4, 8.4 Hz, 0.5 H, rotamer), 1.46 (app d, J=6.8 Hz, 3H),1.45 (s, 9H).Step C:

To a THF solution of LHMDS (1.0 M, 36.5 mL, 36.5 mmol) at 0° C. wasadded indene (2.02 g, 17.4 mmol) in THF (10 mL), dropwise. The reactionmixture was stirred at 0° C. for 50 min., then the dichloride preparedas described in Step B above (4.45 g, 17.4 mmol) was added in THF (15mL), dropwise over 5-6 min. The resulting purple solution was stirred at0° C. for 45 min., then warmed to rt and stirred for 48 h. The reactionmixture was diluted with ethyl acetate and washed with brine. Theorganic layer was dried over MgSO₄, filtered, and concentrated.Purification by MPLC, eluting with 20% ethyl acetate/hexane, afforded3.71 g (71%) of clear oil. ESI-MS calc. for C19H25NO2: 299; Found: 300(M+H).Step D:

The Bocpiperidine prepared in Step C (3.66 g, 12.2 mmol) was dissolvedin anhydrous 4 N HCl (30 mL, 120 mmol) and stirred at rt for 45 min. Thereaction mixture was concentrated to give 2.93 g crude product. ¹H NMRanalysis indicated that the product was a 93:7 ratio of trans to cisisomers.

¹H NMR trans (CD₃OD, 400 MB): δ 7.20-7.37 (m, 4H), 6.95 (d, I=5.6 Hz,1H), 6.80 (d, J=6.0 Hz, 1H), 3.52 (m, 1H), 3.42 (ddd, J=12.8,4.0, 1.2Hz, 1H), 3.29 (m, 1H), 3.07 (t, J=12.8 Hz, 1H), 2.48 (m, 1H), 2.37 (dt,J=4.4, 14.4 Hz, 1H), 1.45 (dt, J=14.4, 2.4 Hz, 1H), 0.40 (d, J=6.8 Hz,3H).

Intermediate 5

Step A:

To a cooled (0° C.) solution of ethanolamine (41.8 g, 0.685 mol) inwater (90 mL) was added neat (R)-propylene oxide (4.97 g, 85.6 mmol),dropwise. After 1 h at 0° C. the reaction was allowed to warm to rt andwas stirred overnight. The reaction mixture was concentrated at ˜80° C.in vacuo to remove the water and most of the ethanolamine, to give 11.79g of crude product, containing some residual ethanolamine. This materialwas used without further purification in Step B.Step B:

The diol prepared in Step A (11.8 g crude [˜86% pure], ca. 83 mmol) wasdissolved in DCM (150 mL) and treated with Boc₂O (23.4 g, 107 mmol) inDCM (75 mL) over 15 min. The reaction mixture was stirred over theweekend, concentrated, and purified by MPLC, eluting with 5% MeOH/EtOActo provide 14.8 g (81%) of product.Step C:

To a solution of the Boc-protected diol prepared in Step B (13.2 g, 60.3mmol) and triethylamine (21.0 mL, 15.3 g, 151 mmol) in DCM (150 mL) at0° C. was added dropwise methanesulfonyl chloride (9.56 mL, 14.1 g, 125mmol). The reaction mixture was then stirred for 1.5 h, diluted withmore DCM (100 mL) and washed with 3N HCl (250 mL). The aqueous layer wasextracted again with DCM (200 mL), and the organic layers were combinedand washed with 1N HCl (250 mL), saturated NaHCO₃ solution (250 mL), andbrine (250 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated to give 22.8 g of crude bis-mesylate, which was usedimmediately. If not used immediately the bis-mesylate underwentdecomposition.Step D:

Indene (7.03 mL, 7.00 g, 60.3 mmol) was added dropwise over 4 min to a1.0 M THF solution of LHMDS (127 mL, 127 mmol) at 0° C. After stirringfor an additional 30 min., this solution was transferred via cannula toa solution of bis-mesylate (22.6 g, 60.3 mmol), prepared as described inStep C above, in THF (75 mL) at 0° C. The mixture was stirred for 2 h,warmed to rt and stirred overnight. The reaction mixture was partiallyconcentrated and then partitioned between ethyl acetate and water. Theorganic layer was extracted again with ethyl acetate and the organiclayers were combined. The organic phase was then washed with brine,dried over MgSO₄, filtered and concentrated to give 17.3 g of crudeproduct. Purification by MPLC, eluting with 15% ethyl acetate/hexane,afforded 9.51 g (53%) of piperidine as a ˜3:1 mixture of trans to cis(determined by H NMR). The mixture was crystallized from hot hexane togive 6 g (33%) of pure trans isomer (>20:1 by H NMR).

¹H NMR (CDCl₃, 400 MHz): δ 7.29 (dt, J=6.4, 1.6 Hz, 1M), 7.20 (m, 3H),6.83 (d, J=6.0 Hz, 1H), 6.67 (d, J=5.6 Hz, 1H), 4.20 (br s, 2H), 2.97(br t, J=3.2 Hz, 1H), 2.69 (br t, J=2.4 Hz, 1H), 2.16 (m, 1H), 2.07 (dt,J=4.4, 13.2 Hz, 111), 1.49 (s, 9H), 1.25 (m, 1H), 0.31 (d, J=6.8 Hz,3H).Step E:

The Boc-piperidine prepared in Step D (4.35 g, 14.5 mmol) was dissolvedin an anhydrous 4 N HCl solution in THF and stirred at rt for 1 h. Thereaction mixture was then concentrated to afford 3.81 g of product.

EI-MS calc. for C14H17N: 199; Found: 200 (M)⁺.

Intermediate 6 was prepared in exactly the same way as intermediate 5except the starting epxide was (S)-(−)-propylene oxide.

H NMR (CD₃OD, 400 MHz): δ 7.22-7.36 (m, 4H), 6.95 (d, J=5.6 Hz, 1H),6.80 (d, J=6.0 Hz, 1H), 3.53 (m, 1H), 3.42 (m, 1H), 3.29 (m, 1H), 3.06(t, J=12.8 Hz, 1H), 2.48 (m, 1H), 2.37 (dt, J=4.4 Hz, 14.4 Hz, 1H), 1.45(dt, J=14.8, 2.4 Hz, 1H), 0.40 (d, J=6.8 Hz, 3H).

Intermediate 7

Step A

A mixture of1-t-butoxycarbonyl-4-trifluoromethanesulfonate-1,2,3,6-tetrahydropyridine(known: Wustrow, D. J., Wise, L. D. Synthesis (1991), 993., 2.50 g, 7.53mmol), triphenylarsine (184 mg, 0.602 mmol), lithium chloride (958 mg,22.6 mmol) and Tris(dibenzylideneacetone)-dipalladium(0) (138 mg, 0.151mmol) in anhydrous 1-methylpyrrolidin-2-one (50 mL) was stirred for 5min, whereupon the reaction color changed from brown/purple to yellow.Then commercially available 3-(tributylstannyl)pyridine (3.27 g, 8.89mmol) was added in anhydrous 1-methylpyrrolidin-2-one (7 mL). Thereaction mixture was purged with argon, stirred at rt for 30 min, at 80°C. for 2.5 h, and at 65° C. for overnight. To the reaction mixture wasadded 1 M KF solution (15 mL) and the resulting mixture was stirred for1 h. The reaction mixture was diluted with ethyl acetate and filteredthrough celite. More 1 M KF solution and ethyl acetate was added to thefiltrate. The layers were separated and the aqueous layer was extractedwith more ethyl acetate. The combined organic layers were washed sixtimes with water, and once with brine, then were dried over anhydrousMgSO₄, filtered, and concentrated. Purification by MPLC (silica, 3%methanol/ethyl acetate) provided 1.09 g (56%) of coupled product. ¹H NMR(400 MHz, CDCl₃): δ 8.63 (d, J=1.6 Hz, 1H), 8.48 (dd, J=4.8, 1.6 Hz,1H), 7.64 (dt, J=8.0, 2.0 Hz, 1H), 7.25 (obsc m, 1H), 6.08 (br s, 1H),4.09 (m, 21), 3.64 (t, J=5.6 Hz, 2H), 2.50 (br s, 2H), 1.47 (s, 9H).Step B

A mixture of 1-t-butoxycarbonyl-4-(3-pyridyl)-1,2,3,6-tetrahydropyridine(1.09 g, 4.19 mmol) and Pd(OH)₂ (20% Pd on Carbon, 220 mg) in ethanol(20 mL) was stirred under a hydrogen atmosphere (balloon) for 5 h. Thereaction mixture was filtered and concentrated, but was found to beincomplete, so was resubmitted to the reaction, this time with 300 mgPd(OH)₂ and under a hydrogen pressure of 50 psi for 7.5 h. The reactionmixture was filtered and concentrated to give 1.12 g of the desiredpiperidine product. ESI-MS calc. for C15H22N2O2: 262; Found: 263 (M+H).Step C

The Boc-piperidine from Step B (1.11 g, 4.23 mmol) was dissolved in 4 NHCl in dioxane (20 mL) and stirred at rt for 1 h. The reaction mixturewas concentrated, redissolved in methanol, filtered through a 0.45 μmPTFE filter, and concentrated again to give 950 mg of piperidinehydrochloride. ¹H NMR (400 MHz, CD₃OD): δ 8.90 (d, J=1.6 Hz, 1H1), 8.80(d, J=6.0 Hz, 1H), 8.66 (dt, J=8.4, 2.0 Hz, 1H), 8.11 (dd, J=8.0, 6.0Hz, 1H), 3.57 (m, 2H), 3.28 (obsc m, 1H), 3.20 (br t, J=13.2 Hz, 2H),2.21 (m, 2H), 2.05 (m, 2H).

Intermediate 8

Step A

According to literature procedures (Wustrow, D. J., Wise, L. D.Synthesis (1991), 9932), N Na₂CO₃ (7 mL) was combined with 3-thiopheneboronic acid (862 mg, 6.73 mmol), lithium chloride (606 mg, 14.4 mmol),1-t-butoxycarbonyl-4-trifluoromethanesulfonate-1,2,3,6-tetrahydropyridine(1.60 g, 4.81 mmol), and tetrakis(triphenylphosphine)-palladium(0) (555mg, 0.481 mmol) in DME (17 mL) under a nitrogen atmosphere. The reactionmixture was warmed to reflux and stirred for 2 h. The reaction mixturewas concentrated, redissolved in DCM, and washed with 2N Na₂CO₃solution, concentrated NH₄OH solution, and brine. The organic layer wasdried over anhydrous MgSO₄, filtered, and concentrated. Purification byflash chromatography (silica, 10% ethyl acetate/hexane) gave 694 mg(55%) of coupled product. ¹H NMR (500 MHz, CDCl₃): δ 7.22 (d, 1H), 7.19(d, 1H), 7.07 (s, 11), 6.00 (br s, 1H), 4.03 (br s, 2H), 3.60 (br s,2H), 2.45 (br s, 2H), 1.47 (s, 9H).Step B

Hydrogenation to the piperidine was accomplished in a similar fashion tothat shown in Step B of the synthesis of Intermediate 7 starting from1-t-butoxycarbonyl-4-(3-thiophene)-1,2,3,6-tetrahydropyridine (694 mg,2.62 mmol) and providing 540 mg of desired product. ESI-MS calc. forC14H21NO2S: 267; Found: 268 (M+H).Step C

Deprotection was accomplished in a similar fashion to that shown in StepC of the synthesis of Intermediate 7 starting from1-t-butoxycarbonyl-4-(3-thiophene)-piperidine (540 mg, 2.02 mmol) andproviding 408 mg of desired product. ESI-MS calc. for C9H13NS: 167;Found: 168 (M+H).

A variety of substituted 4-phenyl piperidines as well 4-heterocyclepiperidines were prepared in the same fashion as described in thesynthesis of Intermediate 8. Some examples are listed in the Tablebelow: Found ESI-MS Intermediate Piperidine Calc. MW (M + H)⁺ 8-1

151 152 8-2

167 168 8-3

195 196 8-4

191 192 8-5

179 180 8-6

179 180 8-7

175 176

Intermediate 9

Formic acid (568 mg, 12.3 mmol) was added to Ac₂O (1.05 g, 10.3 mmol) at0° C. and the resulting mixture was warmed to 60° C., stirred for 2.75 hand cooled to room temperature. THF (5 mL) was then added, the solutionwas cooled to −15° C., and the2-(1-t-butoxycarbonylpiperidin-4-ylamino)aniline (2.00 g, 6.86 mmol) wasadded in THF (5 mL). After 0.5 h the reaction mixture was concentrated(with warming at 40° C.) and the resulting crude product was purified byMPLC (silica, 90% ethyl acetate/hexane, then 100% ethyl acetate, then 4%methanol/ethyl acetate) to give 1.25 g of the benzimidazole. The BOCgroup was removed by dissolving the intermediate (1.21 g, 4.00 mmol) inethyl acetate and bubbling HCl (g) through this solution for 10 min. Thesolvent was removed to afford 962 mg of crude Intermediate 10 as itshydrochloride salt.

BOC intermediate: ESI-MS calculated for C17H23N3O2: 301; Found: 302(M+H).

Intermediate 10

Step A

N-Boc-isonipecotic acid (8.04 g, 35.1 mmol) was combined withN,O-dimethylhydroxylamine hydrochloride (5.13 g, 52.6 mmol), EDC (10.1g, 52.6 mmol) and DIEA (9.2 mL, 53 mmol) in DCM (100 mL). ThenN,N-dimethylaminopyridine (˜200 mg) was added and the reaction mixturewas permitted to stir at rt for 2 h. The reaction mixture was dilutedwith more DCM and washed with 2 N HCl solution, saturated NaHCO₃solution, and brine. The organic layer was dried over anhydous MgSO₄,filtered, and concentrated to give 8.43 g of crude product which wasused without further purification. ESI-MS calc. for C13H24N2O4: 272;Found: 273 (M+H).Step B

A cooled (−78° C.) solution of the amide prepared as described in Step A(8.35 g, 30.7 mmol) in 100 mL ether was treated dropwise with 3.0 Mmethylmagnesium chloride in THF (20.4 mL, 61.3 mmol) over a period offive min. The resulting thick slurry was warmed to 0° C. and stirred for0.5 h. The reaction mixture was poured into 1 N HCl solution andextracted with ether. The ethereal layer was washed with brine, driedover anhydrous MgSO₄, filtered, and concentrated to give 5.81 g of crudeproduct which did not require further purification.Step C

To a cooled (−78° C.) solution of 2.0 M LDA (in heptane/THF/benzene,13.7 mL, 27.3 mmol) in 100 mL THF was added dropwise over 40 min asolution of the methyl ketone prepared as described in Step B (5.17 g,22.8 mmol) in 40 mL THF. After an additional 25 min,chlorotrimethylsilane (5.79 mL, 45.6 mmol) was added dropwise over 10minutes. After stirring the for 1 h, the reaction mixture was pouredinto 300 mL of saturated NaHCO₃ solution and the resulting mixture wasextracted twice with 200 mL of ether. The combined ethereal layers werewashed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated to give 7.35 g of TMS-enol ether, which was thenredissolved in 120 mL THF, cooled to 0° C., and treated with sodiumbicarbonate (2.87 g, 34.2 mmol), followed by N-bromosuccinimide (4.06 g,22.8 mmol). The reaction mixture was warmed to rt and stirred for 1 hand 10 min, at which point, it was poured into 200 mL of saturatedNaHCO₃ solution. The resulting mixture was extracted twice with 200 mLof ether and the combined ethereal layers were washed with saturatedNaHCO₃ solution and brine, dried over anhydrous MgSO₄, filtered, andconcentrated to give 7.62 g of crude product which was used withoutfurther purification.Step D

The bromomethylketone prepared as described in Step C (1.48 g, 4.83mmol) was combined with thioformamide (295 mg, 4.83 mmol) in 10 mL ofTHF. The reaction mixture was warmed to 60° C. and stirred for 4 days.The reaction mixture was then diluted with ethyl acetate and washed withwater, then brine, dried over anhydrous MgSO₄, filtered, andconcentrated. Purification by MPLC (silica, 60% ethyl acetate/hexane)afforded 627 mg of thiazole product. ¹H NMR (400 MHz, CDCl₃): δ 8.75 (d,J=2.0 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 4.19 (br s, 2H), 2.96 (m, 1H),2.84 (br m, 2H), 2.03 (m, 2H), 1.62 (m, 2H), 1.44 (s, 9H).Step E

The thiazole prepared as described in Step D (588 mg, 2.19 mmol) wastreated with 4 N HCl in dioxane (15 mL). Since the mixture washeterogeneous, 1 mL of water was added to solubilize the startingmaterial and the mixture was stirred for 1.5 h. The reaction mixture wasthen concentrated to give 526 mg of piperidine hydrochloride. ¹H NMR(400 MHz, CD₃OD): δ 9.60 (d, J=2.4 Hz, 1H), 7.72 (d, J=2.80 Hz, 1H),3.52 (m, 2H), 3.31 (m, 1H), 3.19 (m, 21), 2.29 (m, 2H), 1.99 (m, 2H).ESI-MS calc. for C8H12N2S: 168; Found: 169 (M+H).

Intermediate 11

Step A

The bromomethylketone prepared as described in Steps A-C of thesynthesis of Intermediate 10 (2.02 g, 6.60 mmol) was combined withformamidine acetate (1.37 g, 13.2 mmol) in ˜130 mL of NH₃ (1) and heatedin an autoclave at 40° C. and 194 psi for 20 h. The NH₃ was allowed toevaporate, the residue was dissolved in DCM and filtered. The filtratewas concentrated. Purification by flash chromatography (silica, 10% of1:9 NH₄OH/methanol in DCM) afforded 649 mg of the imidazole product.

¹H NMR (400 MD, CD₃OD): δ 7.56 (d, J=1.2 Hz, 1H), 6.74 (d, J=1.2 Hz,1H), 4.13 (br s, 2H), 2.82 (m, 2H), 2.74 (m, 1), 1.97 (m, 2H), 1.54 (m,2H), 1.44 (s, 9).Step B

The intermediate from Step A (402 mg, 1.60 mmol) was dissolved in 4N HClin dioxane (5 mL) and stirred at rt for 1.5 h. The reaction mixture wasconcentrated to afford 384 mg of piperidine hydrochloride. ESI-MS calc.for C8H13N3: 151; Found: 151 (M+).

EXAMPLE 1

The crude aldehyde intermediate 1 (107 mg, 0.255 mmol), prepared asdescribed above, was combined with 4-phenylpiperidine (49.3 mg, 0.306mmol), NaB(OAc)₃H (108 mg, 0.510 mmol) and 4° A molecular sieves (250mg) in DCE (5 mL) and stirred overnight. The reaction mixture wasfiltered through celite, diluted with ethyl acetate, and washed withsaturated, NaHCO₃ solution, followed by brine. The organic layer wasdried over MgSO₄, filtered, and concentrated. The crude product waspurified by preparative LC, eluting with 0.75/6.75/92.5 NH₄OH/MeOH/DCM,providing the product as a free base. H NMR (CDCl₃, 400 MHz): δ 7.71 (s,1H), 7.64 (s, 2H), 7.28-7.37 (m, 4H), 7.21 (m, 3H), 7.01 (m, 2H), 4.51(m, 2H), 4.15 (br s, 1H), 3.20-3.33 (m, 2H), 2.32-2.75 (m, 6H), 2.21 (brm, 2H), 2.05 (m, 1H), 1.93 (m, 2H). The free base was converted to itsHCl salt by dissolving it in DCM (2 mL) and adding anhydrous 4 N HCl indioxane (70 μL, 0.3 mmol), then concentrated off the solvents to give50.2 mg (33%) of a white solid. ESI-MS calc. for C30H29F7N2O: 566;Found: 567 (M+H).

EXAMPLE 2

The enantiomer of the compound prepared as described in EXAMPLE 1 wasprepared in exactly the same way except that in the preparation of thecorresponding enantiomer of Intermediate 1, (R)-(+)-α-methylbenzylaminewas used instead of (S)-(−)-α-methylbenzylamine in the resolution of theracemic carboxylic acid. ESI-MS calc. for C30H29F7N2O: 566; Found: 567(M+H).

Additional compounds were prepared essentially using the sameexperimental protocols as described in EXAMPLE 1 are displayed in Tables1 and 2. Requisite amines incorporated via the reductive amination stepare either commercially available, known from the chemical literature,or were prepared as described above. TABLE 1 ESI-MS Found Entry Aminecalc. MW (M + H)⁺ 1-1

490 491 1-2

581 582 1-3

567 568 1-4

580 581 1-5

584 585 1-6

582 583 1-7

532 533 1-8

577 578 1-9

582 583 1-10

638 639 1-11

591 592 1-12

552 553 1-13

580 581 1-14

562 563 1-15

597 598 1-16

605 606 1-17

584 585 1-18

584 585 1-19

596 597 1-20

596 597 1-21′

580 581 1-22

592 593 1-23

572 573 1-24

572 573 1-25

556 557 1-26

573 574 1-27

556 557 1-28

567 568 1-29

567 568 1-30

580 581 1-31

580 581 1-32

580 581 1-33

601 602 1-34

581 582 1-35

565 566

TABLE 2 Spiropiperidines

ESI-MS Found Entry Amine calc. MW (M + H)⁺ 1-36

590 591 1-37

592 593 1-38

604 605 1-39

594 595 1-40

696 697 1-41

610 611 1-42

635 636 1-43

570 571 1-44

618 619 1-45

604 605 1-46

604 605 1-47

604 605

EXAMPLE 3

Step A:

Sulfuric acid (7.28 mL, 137 mmol) was added to a suspension of MgSO₄(65.6 g, 547 mmol) in DCM (˜500 mL). After stirring for 30 min,4-fluorophenylacetic acid (18.6 g, 137 mmol) was added, followed byt-butanol (65.3 mL, 683 mmol). The reaction mixture was stirredvigorously for 23 h, then was quenched with saturated NaHCO₃ solution(until MgSO₄ had dissolved). The mixture was extracted with DCM, thenthe organic layer was washed with brine, dried over anhydrous MgSO₄,filtered, and concentrated to give 22.4 g of crude ester. A cooled (−78°C.) solution of the resulting t-butyl ester (10.0 g, 47.6 mmol) in THF(˜75 mL) was treated dropwise with 1M lithium hexamethyldisilazidesolution in THF (143 mL, 143 mmol), stirred for an additional 30 min,then treated dropwise with 3-bromo-2-methylpropene. The reaction mixturewas allowed to slowly warn to rt over a period of 1.5 h. The reactionmixture was quenched with water and concentrated. The residue wasredissolved in ethyl acetate and washed with 1N HCl solution, thenbrine. The organic layer was dried over anhydrous MgSO₄, filtered, andconcentrated to give 12.3 g of desired title compound, which did notrequire further purification.

H NMR (CDCl₃, 500 MHz): δ 7.31 (m, 2H), 7.01 (m, 2H), 4.79 (s, 1H), 4.73(s, 1H), 3.68 (m, 1H), 2.79 (m, 1), 2.38 (m, 1H), 1.74 (s, 3H), 1.40 (s,9H).Step B:

Ozone was bubbled through a cooled (−78° C.) solution of the olefin fromStep B (4.0 g, 15 mmol) in methanol until a green/blue color persisted.Nitrogen was bubbled through the solution until the blue color hasdisappeared. Then sodium borohydride (576 mg, 15.2 mmol) was added andthe mixture was stirred for 1.5 h. The reaction mixture was quenchedwith water and concentrated to remove the methanol. The resultingaqueous mixture was extracted with ethyl acetate and the organic layerwas washed with 1 N HCl solution and brine, dried over anhydrous MgSO₄,filtered, and concentrated to give 2.37 g of product which was notfurther purified (˜6:4 ratio of diastereomers). H NMR (CDCl₃, 500 MHz):δ 7.32 (m, 2H), 7.02 (m, 2H), 3.70 (m, 1.4H), 3.47 (m, 0.6 H), 2.15 (m,1H), 2.07 (m, 1H), 1.80 (m, H1), 1.63 (m, 1H), 1.38 (s, 9H), 1.18 (d,1.2H), 1.15 (d, 1.8H).Step C:

To a cooled (0° C.) solution of the alcohol prepared as described inStep B (1.19 g, 4.46 mmol), 4-phenyl glutarimide (1.04 g, 5.35 mmol),and triphenylphosphine (1.40 g, 5.35 mmol) in THF (20 mL) was added asolution of diisopropyl azodicarboxylate (1.05 mL, 5.35 mmol). Thereaction mixture was permitted to warm to rt and stir for 3 h. Thereaction mixture was concentrated, redissolved in ethyl acetate, andwashed with saturated NaHCO₃ solution, then brine, dried over anhydrousMgSO₄, filtered, and concentrated. Purification by flash chromatography(silica, 50% ethyl acetate/hexane), followed by MPLC (silica, 75% ethylacetate/hexane) gave 968 mg of the desired product.Step D:

To a cooled solution (0° C.) solution of the glutarimidoester preparedas described in Step C (544 mg, 1.24 mmol) in THF (5 mL) under an N₂atmosphere was added borane dimethylsulfide complex (0.372 mL, 3.72mmol). The resulting mixture was warmed to rt and stirred for 3 h. Thereaction mixture was concentrated and N,N-dimethylethanolamine (3.73 mL,37.2 mmol) was added. The resulting mixture was stirred at reflux for 2h, then concentrated. Purification by preparative TLC (silica, 1% of 1:9NH₄OH/methanol in DCM) furnished 275 mg of piperidine product (54%).

ESI-MS calc. for C26H34FNO2: 411; Found: 412 (M+H).Step E:

A solution of the piperidine ester prepared as described in Step D (30mg, 0.073 mmol) in 4 N HCl in dioxane (−3 ml) was stirred overnight atrt., then concentrated to give 25 mg of acid which required no furtherpurification (96%). ESI-MS calc. for C22H26FNO2: 355; Found: 356 (M+H).Step F:

The acid from Step E (21 mg, 0.059 mmol) was combined with3,5-Bis(trifluoromethyl)benzylamine hydrochloride (17 rag, 0.071 mmol),EDC (14 mg, 0.071 mmol), and triethylamine (20 μL, 0.15 mmol) in DCM (2mL). After 30 min, HOAt (10 mg, 0.071 mmol) was added and the reactionmixture was stirred for 72 h. The reaction mixture was diluted with DCMand washed with saturated NaHCO₃ solution and brine. The aqueous layerwas back-washed with more DCM and the combined organic layers were driedover anhydrous MgSO₄, filtered, and concentrated. Purification bypreparative TLC (silica, 2% of 1:9 NH₄OH/methanol in DCM) furnished 18mg of amide product ESI-MS calc. for C31H31F7N2O: 580; Found: 581 (M+H).

Intermediate 12

Step A

To a solution of lithium bis(trimethylsilyl)amide, LHMDS, (11.38 g, 68.0mmol) in THF (100 ml) cooled to −78° C. by dry ice/acetone bath wasadded phenyl acetic acid (8.05 g, 59.16 mmol) in 40 ml THF via syringeand the resulting mixture stirred for one hour. The mixture was treatedwith 2,2-dimethyoxy-1-bromoethane (10 g, 59.16 mmol) and stirredovernight allowing to warm to room temperature. The reaction wasquenched with a saturated solution of ammonium chloride (100 ml) and theresulting mixture was poured into a separatory funnel. The organic layerwas separated, washed with brine (1×50 mL), dried with anhydrous sodiumsulfate and the solvent was evaporated in vacuo to yield 11.50 g (87%)of the crude product. The crude residue was purified by flash column(gradient eluant 20% ethyl acetate/hexane to 60%.ethyl acetate/hexane)to yield 9.0 g (68%) of the racemic desired product. The desired Sisomer was obtained through crystallization with (R) (+)-alpha methylbenzylamine (2.55-ml, 20.11 mmol, 0.5 eq) in ether (80 ml) cooled byrefrigeration overnight. The solid white precipitate was filtered andwashed with cold ether, then dissolved in ethyl acetate (200 ml) andwashed with 0.5N HCl (2×50 ml). The organic layer was dried overanhydrous sodium sulfate and the solvent was evaporated in vacuo toyield 3.47 g (26%) of the title compound. ¹H NMR (500 MHz, CDCl₃): 4.28(dd, J=6.4, 8.0 Hz, 1H), 3.75 (dd, J=7.1, 8.0, 1H), 3.26 (s, 3H), 3.24(s, 3H), 2.50-2.43 (m, 1H), 2.07-2.00 (m, 1H).Step B

A mixture of the acid (described in step A, 1.0 g, 4.46 mmol),3,5-bis(trifluoromethyl)benzylamine hydrochloride (1.25 g, 4.46 mmol),HOBt (602 mg, 4.46 mmol), N,N-diisopropyl ethylamine (776 μl, 4.46 mmol)in dichloromethane (20 mL) was treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 1.71g, 8.92 mmol) and stirred at room temperature overnight. The reactionmixture was diluted with dichloromethane (30 mL), washed with water(2×20 mL), brine (1×30 mL), dried over anhydrous sodium sulfate and thesolvent was evaporated. The pure compound was obtained by MPLCpurification (eluant 20% ethyl acetate/hexane), 1.62 g (81%). LC-MS: forC₂₁H₂₁NO₃F₆ [M+H] calculated 449.14, found 450.Step C

The intermediate in Step B (1.0 g, 2.23 mmol) was treated with solutionof 90% trifluoroacetic acid/water (20 ml) for 10 minutes. The reactionmixture was diluted with water (30 mL) and extracted with ether (3×40ml). The organic layer was washed with saturated sodium bicarbonate(3×50 mL), brine (1×50 mL), dried over anhydrous sodium sulfate and thesolvent was evaporated in vacuo to yield 512 mg (57%) of the crudeproduct. No further purification was done and the material was storedunder a blanket of nitrogen in the freezer (−16° C.).

EXAMPLE 4

A solution of Intermediate 12 (Intermediate 12, 100.0 mg, 0.256 mmol)spiroindenylpiperidine hydrochloride (70.0 mg, 0.315 mmol),diisopropylethylamine (55 μL, 0.315 mmol) and crushed molecular sieves(4A, 50 mg) in dichloroethane (5 mL) was treated with sodiumtriacetoxyborohydride (378 mg, 1.783 mmol) and stirred at roomtemperature overnight. The sieves were filtered off (plug of Celite),washed with dichloromethane and the combined organic washings wereextracted with a saturated solution of sodium bicarbonate (1×10 mL),water (2×10 mL), brine (1×10 mL) and dried over anhydrous sodiumsulfate. The solvent was evaporated to dryness to yield 133 mg (91%) ofthe crude product. The residue was purified by preparative TLC (eluent:100% ethyl acetate) to yield 105.2 mg (72%) of the final pure desiredproduct. LC-MS for C₃₂H₃₀N2OF₆ [M+H]⁺ calculated 572.24, found 573.

Additional compounds were prepared in a similar fashion as Example 4above, with the modification of replacing phenylacetic acid withvariably substituted phenylacetic acids, as appropriate. TABLE 4

FW: formula/found Entry R (M + H) 4-1

C₃₂H₂₉N₂OClF₆ 607 4-2

C₃₂H₂₉N₂OF₇ 591 4-3

C₃₂H₂₉N₂OF₇ 591

EXAMPLE 5

A solution of Intermediate 12 (intermediate 12, 100.0 mg, 0.256 mmol)4-phenylpiperidine hydrochloride (70.0 mg, 0.354 mmol),diisopropylethylamine (62 μL, 0.354 mmol) and crushed molecular sieves(4A, 50 mg) in dichloroethane (5 mL) was treated with sodiumtriacetoxyborohydride (378 mg, 1.78 mmol) and stirred at roomtemperature overnight. The sieves were filtered off (plug of Celite),washed with dichloromethane and the combined organic washings wereextracted with a saturated solution of sodium bicarbonate (1×10 mL),water (2×10 mL), brine (1×10 mL) and dried over anhydrous sodiumsulfate. Solvent was evaporated to dryness to yield 120 mg (86%) of thecrude product. The residue was purified by preparative TLC (eluent: 5%methanol/95% ethyl acetate) to yield 84.6 mg (60%) of the final puredesired product.

LC-MS for C₃₂H₃₀N₂₀F₆ [M+H]⁺ calculated 548.23, found 549.

Additional compounds were prepared in a similar fashion as Example 5above, with the modification of replacing phenylacetic acid withvariably substituted phenylacetic acids, as appropriate. TABLE 5

FW: formula/found Entry R (M + H) 5-1

C₃₀H₂₉N₂OClF₆ 583 5-2

C₃₀H₂₉N₂OF₇ 567

Intermediate 13

Step A

A solution of 4-methoxyphenylacetic acid (5.0 g, 30.088 mmol) intetrahydrofuran (50 mL) was added drop-wise onto a suspension of sodiumhydride (1.60 g, 40.20 mmol, 60%) in THF (50 mL), and then heated toreflux for 2 hrs. The suspension of the salt was cooled to 10° C. and asolution of lithium diisopropylamid (generated from 4.64 mL, 33.09 mmol)of diisopropylamine and 21.0 mL of nBuLi (1.6 M, hexanes)) in 50 mL oftetrahydrofuran was added via canula. The reaction mixture was allowedto warm up to room temperature and stirring was continued for another 2hrs. To this slurry was added neat allyl bromide (2.86 mL, 33.09 mmol)via syringe. The temperature rose spontaneously to app. 45° C., and wasstirred at room temperature overnight. The reaction mixture was dilutedwith diethyl ether (100 mL), and extracted with water (1×50 mL). Theaqueous layer was washed with diethyl ether two more times. The combinedorganic extracts were dried (anhydrous magnesium sulfate) to yield afterevaporation 5.74 g (93%) of the crude acid. This was used without anyadditional purification in the subsequent step.Step B

Starting with the acid from Step A and3,5-bistrifluoromethylbenzylamine, this amide was synthesized in ananalogous fashion to the procedure described in Step B, synthesis ofIntermediate 1, except that HOAt was used in place of HOBt. MS: forC₂₁H₁₉NO₂F₆ [M+H]⁺ calculated: 432.13, found 432.4.Step C

The olefin (980 mg, 2.27 mmol) was ozonized at −78° C. indichloromethane until permanent blue color indicated completeconsumption of the olefin. The excess ozone was purged with a stream ofnitrogen, and the ozonide was reduced with dimethylsulfide (1.6 mL,122.7 mmol). The cooling bath was removed, and the reaction mixture wasgradually warmed up to room temperature. The solvent and excess of DMSwas concentrated, and the resulting residue was used in the nextreaction without purification.

EXAMPLE 6

Example 6 was synthesized starting from aldehyde Intermediate 13 and4-spiroindenylpiperidine hydrochloride according to a proceduredescribed for preparation of Example 1, except that 1.2 equivalents ofDIEA was added and the solvent was DCM instead of DCE. MS: forC₃₃H₃₂N₂O₂F₆ [M+H]⁺ calculated: 603.24, found 603.20.

EXAMPLE 7

Example 7 was synthesized starting from acid Intermediate 13 and4-phenylpiperidine hydrochloride according to the procedure describedfor preparation of Example 6. MS: for C₃₁H₃₂N₂O₂F₆ [M+H]⁺ calculated:579.24, found 579.00.

EXAMPLE 8

A solution of Example 7 (100 mg, as hydrochloride, 0.163 mmol) wasdissolved in dry dichloromethane (10 mL), and treated at 0° C. with neatboron tribromide (980 μL, 0.975 mmol). After stirring at 0° C. for 30minutes the temperature was allowed warm up to ambient, and stirring wascontinued for another 3 hrs. The reaction mixture was cooled again to 0°C. and quenched with ammonium hydroxide (4.0 mL, 30% aq. Solution).After 30 minutes of stirring the product was extracted withdichloromethane (3×20 mL). After drying (anhydrous sodium sulfate) thesolvent was removed in vacuo to leave 93 mg (100%) of the desiredphenol. MS: for C₃₀H₃₀N₂O₂F₆ [M+H]⁺ calculated: 565.22, found 565.00.

EXAMPLE 9

Example 9 was prepared using the synthetic sequence described forpreparation of Example 7 except that 3-methoxyphenylacetic acid was usedinstead of 4-methoxyphenylacetic acid. MS: for C₃₁H₃₂N₂O₂F₆ [M+H]⁺calculated: 579.24, found 579.2.

EXAMPLE 10

Example 10 was prepared using the synthetic sequence described forpreparation of Example 6 except that 3-methoxyphenylacetic acid was usedinstead of 4-methoxyphenylacetic acid. MS: for C₃₃H₃₂N₂O₂F₆ [M+H]⁺calculated: 603.24, found 646.5.

EXAMPLE 11

Step A

Thionyl Chloride (1.61 mL, 22.1 mmol) was pipetted dropwise intomethanol (75 mL) in a 250 mL round-bottomed flask. Then a solution of3-nitrophenylacetic acid (2 g, 11.0 mmol) in methanol (10 mL) was added.The mixture was refluxed for 1 hour and concentrated in vacuo to yield11-A (2.12 g, 98.6%). The crude product was used on the next step.Step B

To a 250 mL round-bottomed flask equipped with a stir bar, septum, andan argon baloon, was suspended sodium hydride 60% (490 mg, 11.8 mmol) inanhydrous DMF (40 mL). A solution of 11-A (2.10 g, 10.8 mmol) inanhydrous DMF (10 mL) was added via syringe. The mixture was cooled to0° C. before allyl bromide (1.22 mL, 14.1 mmol) was added. The reactionwas slowly warmed up to room temperature and stirred overnight. Themixture was diluted with ether, washed with water and brine, dried overanhydrous magnesium sulfate, and concentrated in vacuo. The crudeproduct was purified by MPLC (20/80: ethyl acetate/hexanes) to yield11-B (2.32 g, 91.3%).Step C

To a solution of 11-B (2.32 g, 9.86 mmol) in MeOH (25 mL) was addedconcentrated HCl (25 mL) followed by Zn dust (12.9 g, 197 mmol) inseveral portions. The reaction mixture was allowed to stir at roomtemperature for 1 hr before filtered through celite to remove the excesszinc. The filtrate was diluted with ethyl acetate and extracted withsaturated NaHCO₃ solution. The organic layer was dried over MgSO₄ andconcentrated in vacuo to yield 11-C (2.62 g, 99⁺%). The crude productwas used in the next step.Step D

To a solution of 11-C (2.39 g, 9.86 mmol) in CH₂Cl₂ (50 mL) was addedDMAP (tare). The mixture was cooled to 0° C. in an ice bath beforedi-tert-butyl dicarbonate (3.24 g, 14.8 mmol) was added slowly. Themixture was stirred at room temperature overnight before concentrated invacuo. The resulting oil was redissolved in ethyl acetate, extractedwith saturated NaHCO₃ solution, washed with brine, dried over MgSO₄, andconcentrated in vacuo. The crude product was further purified by a flashcolumn (10/90 ethyl acetate/hexanes) to yield 11-D (1.12 g, 37.1% forlast two steps).Step E

A solution of 11-D (1.12 g, 3.67 mmol) in CH₂Cl₂ (25 mL) was cooled to−78° C. in a dry ice/acetone bath before ozone was bubbled in from anozonator. After the mixture turned a gray-blueish color, nitrogen gaswas bubbled in until the solution was colorless. Methyl sulfide (2.70mL, 36.7 mmol) was added and the solution was allowed to stir at −78° C.for an additional 30 minutes. The reaction mixture was warmed up to roomtemperature and concentrated in vacuo. The concentrate was diluted withwater and extracted with ether (5×), dried over MgSO₄, and concentratedin vacuo to yield a crude product of 11-E (1.13 g) which was immediatelyused on next step.Step F

11-E (1.13 g, 3.67 mmol), spiralenedine (813 mg, 2.67 mmol), DIEA (639μL, 3.67 mmol) were dissolved in Dichloro methane. Molecular sieves wereadded to eliminate water, and sodium triacetoxy-borohydride (3.9 g, 18.4mmol) was added. The mixture was stirred overnight, then was quenchedwith a saturate NaHCO₃ solution, washed with brine, dried over MgSO₄,and concentrated in vacuo. Purification with a flash column (20/80 ethylacetate/hexane) yielded 11-F (1.32 g, 75.4% over two steps).Step G

11-F (1.32 g, 2.77 mmol) was dissolved in THF (5 mL), MeOH (5 mL), andH₂O (5 mL). Lithium hydroxide (232 mg, 5.54 mmol) was added. Thereaction mixture was stirred and monitored by TLC. After completion ofreaction, the mixture was concentrated in vacuo and redissolved in H₂O.pH of the solution was adjusted to 7.0 by 2N HCl and extracted withCH₂Cl₂ (5×). The combined organic layer was dried over MgSO₄ andconcentrated in vacuo to yield 11-G (890 mg, 69.5%). The crude productwas used in the next step.Step H

EXAMPLE 11

The acid 11-G (890 mg, 1.92 mmol), 3,5-bistrifluoromethylbenzylaminehydrochloride (538 mg, 1.92 mmol), Hunnig's base (1.34 mL, 7.68 mmol),HOAt (261 mg, 1.92 mmol), EDC (552 mg, 2.88 mmol), and DCM were stirredovernight before washing with 1N NaOH solution and brine. The organiclayer was dried over MgSO₄ and concentrated in vacuo. The crude productwas purified by a flash column (100% ethyl acetate) to yield Example 11(747 mg, 53.7%). LC-MS.: MW calculated 687.71, found 688.3.

EXAMPLE 12

Example 11 (640 mg, 0.93 mmol) and TFA (7 mL) were combined and stirredfor half hour before concentrating in vacuo. The crude product wasredissolved in DCM and salted out with 4N HCl in dioxane to yieldExample 12 (600 mg, 99⁺%). LC-MS: MW calculated 587.6, found 588.4.

A variety of N-substituted derivatives of Example 12 were synthesized.These compounds were made by simple coupling reactions known to thoseskilled in the art. Table 6 below summarizes these compounds. TABLE 6

Calc'd ESI-MS found Example R MF MW (M + H)⁺ 12-1 COCH₃ C₃₄H₃₃F₆N₃O₂ 629630 12-2 CO₂CH₃ C₃₄H₃₃F₆N₃O₃ 645 646 12-3 SO₂CH₃ C₃₄H₃₃F₆N₃O₃S 665 66612-4 CONHCH₃ C₃₄H₃₄F₆N₄O₂ 644 645 12-5 CONHCH₂CH₃ C₃₅H₃₆F₆N₄O₂ 658 65912-6 CONH₂ C₃₃H₃₂F₆N₄O₂ 630 631

EXAMPLE 13

Step A

Potassium bis(trimethylsilyl)amide (7.17 g, 35.9 mmol) was dissolved inanhydrous THF (55 in L) under argon. The mixture was cooled to −78° C.before a solution of 3-bromophenylacetic acid (3.09 g, 14.4 mmol) in THF(15 mL) was added dropwise via an addition funnel. The mixture wasstirred for another 30 minutes before allyl bromide (1.87 mL, 21.6 mmol)was added. The reaction was monitored by TLC. After the completion ofthe reaction, the mixture was concentrated in vacuo and redissolved inwater. The aqueous layer was washed with ether, acidified by citricacid, and extracted by ethyl acetate. The organic layer was dried overMgSO₄ and concentrated in vacuo. The crude product was purified by MPLC(50/50 ethyl acetate/hexanes) to yield 13-A (3.18 g, 86.9%).Step B

Thionyl chloride (1.8 mL, 24.4 mmol) was pipetted dropwise into methanol(60 mL) in a 250 mL round-bottomed flask. Then a solution of 13-A (3.10g, 12.2 mmol) in methanol (10 mL) was added. The mixture was stirred atreflux for 30 minutes and concentrated in vacuo to yield 13-B (3.21 g,98.2%). The crude product was used on the next step.Step C

A solution of 13-B (3.0 g, 11.1 mmol) in CH₂Cl₂ (50 mL) was cooled to−78° C. before ozone was bubbled in from an ozonator. After the mixtureturned gray-blue in color, nitrogen gas was bubbled in until thesolution was colorless. Methyl sulfoxide (8.15 mL, 11.1 mmol) was addedand the solution was allowed to stir at −78° C. for an additional 30minutes. The reaction mixture was warmed up to room temperature andconcentrated in vacuo. The concentrate was diluted with water andextracted with ether (5×), dried over MgSO₄, and concentrated in vacuoto yield a crude product of 13-C (3.0 g, 100%) which was immediatelyused in the next step.Step D

13-C (100 mg, 0.369 mmol), spiralenedine (81.8 mg, 0.369 mmol), and DIEA(64.3 μL, 0.369 mmol) were dissolved in DCE. Molecular sieves were addedto eliminate water and sodium triacetoxyborohydride (392 mg, 1.85 mmol)was added last. The mixture was stirred overnight, then quenched with asaturate NaHCO₃ solution, washed with brine, dried over MgSO₄, andconcentrated in vacuo. Purification by preparative TLC (40/60 ethylacetate/hexane) yielded 13-D (133 mg, 82.1%).Step E

DMF (2 mL) was deoxygenated by bubbling with nitrogen for 30 minutesbefore a solution of 13-D (125 mg, 0.284 mmol) in DMF (1 mL) was added.The solution was bubbled with nitrogen for another 15 minutes thenZn(CN)₂ and Pd(PPh₃)₄ were added. After bubbling in nitrogen for anadditional 15 minutes, the mixture was heated to 80° C. and stirredovernight. The reaction mixture was diluted with ethyl acetate, washedwith NH₄OH (2×), and concentrated in vacuo. The crude product waspurified by preparative TLC (40/60 ethyl acetate/hexanes) to yield 13-E(52 mg, 47.3%). LC-MS: MW calculated 386.49, found 387.2.Step F

13-D (52 mg, 0.135 mmol) was first dissolved in a solution of THF (1mL), MeOH (1 mL), and H₂O (1 mL). The mixture was cooled to 0° C. beforeLiOH (23 mg, 0.538 mmol) was added. The solution was stirred at 0° C.for 1 hour before raised to room temperature and stirred overnight. Thereaction mixture was concentrated in vacuo and the residue wasredissolved in a minimum amount of H₂O. After the pH was adjusted to 7.0with 2N HCl, the aqueous layer was extracted with DCM (5×). The combinedorganic layers were concentrated in vacuo to yield the crude 13-F (38.7mg, 77.4%), which was used on next step.Step G

EXAMPLE 13

Intermediate 13-F (38.7 mg, 0.104 mmol), spiroindenepiperidinehydrochloride (29.1 mg, 0.104 mmol), Hunnig's base (72 μL, 0.416 mmol),HOAt (14.2 mg, 0.104 mmol), and EDC (30 mg, 0.156 mmol) in DCM werestirred overnight then washed with 1N NaOH solution and brine. Theorganic layer was dried over MgSO₄ and concentrated in vacuo. The crudeproduct was purified by preparative TLC (60/40 ethyl acetate/hexanes) toyield Example 13 (747 mg, 53.7%). LC-MS: MW calculated 597.22, found598.3.

EXAMPLE 14

Step A

14-A was prepared as detailed in Example 13 (Steps F & 0) using 13-D asthe starting material.Step B

EXAMPLE 14

A mixture of 14-A (444 mg, 0.682 mmol), Pd(dppf).DCM (56 mg, 0.068mmol), Et₃N (190 μL, 1.36 mmol), DMF (7 mL), and MeOH (3 mL) wasprepared under CO balloon. The mixture was stirred and heated at 95° C.overnight. The solid was filtered out and solvent was concentrated invacuo. The concentrated was redissolved in H₂O, extracted with ethylacetate, dried over MgSO₄, and concentrated in vacuo. The crude productwas further purified by preparative TLC (60/40 ethyl acetate/hexanes) toyield Example 14 (187 mg, 43.5%). LC-MS: MW calculated 630.62, found631.4.

EXAMPLE 15

Example 14 (187 mg, 0.297 mmol) was first dissolved in a solution of THF(2 mL), MeOH (2 mL), and H₂O (2 mL). The mixture was cooled to 0° C.before LiOH (25 mg, 0.594 mmol) was added. The solution was stirred at0° C. for 10 minutes before warming to room temperature and stirring foranother 4 hours. TLC showed starting material so 1 eq of NaOH was addedto push the reaction to completion. The reaction mixture wasconcentrated in vacuo and redissolved in DCM. A few drops of 4N HCl indioxane was added and the mixture was concentrated and purified bypreparative TLC (80/20 ethyl acetate/hexanes) to yield Example 15 (20mg, 10.9%). LC-MS: MW calculated 616.59, found 617.4.

EXAMPLE 16

The product from Example 15 (18 mg, 0.029 mmol), ethylamine 2M (15 μL,0.029 mmol), HOAt (4 mg, 0.029 mmol), EDC (9 mg, 0.044 mmol), and DCMwere stirred overnight before washing with 1N NaOH. The organic layerwas dried over MgSO₄ and concentrated in vacuo. The crude product waspurified by preparative TLC (silica, 100% ethyl acetate) to yieldExample 16. LC-MS: MW calculated 643.26, found 644.4.

Intermediate 14

A solution of 4-pentenoic acid (100 mg, 1.0 mmol),3,5-bis(trifluoromethyl)benzylamine hydrochloride (279 mg, 1.0 mmol),HOAt (136 mg, 1.0 mmol), and N,N-diisopropyl ethylamine (174 μl, 1.0mmol) in dichloromethane (10 mL) was treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 382mg, 2.0 mmol) and stirred at room temperature overnight. The reactionmixture was diluted with dichloromethane (20 mL), washed with water(2×20 mL), brine (1×20 mL), dried over anhydrous sodium sulfate and thesolvent was evaporated. Purification was accomplished by preparative TLC(eluant: 40% ethyl acetate/hexane) to yield 295 mg (90%) of the desiredproduct.

EXAMPLE 17

A solution of Intermediate 14 (100 mg, 0.307 mmol) in dichloromethane(5mL) was cooled to −78° C. and a stream of ozone was passed throughuntil a permanent blue color indicated complete consumption of theolefin. The excess ozone was purged with a stream of nitrogen and thereaction mixture was allowed to warm up to ambient temperature. Thesolution was dried with magnesium sulfate, the drying agent was filteredoff, and to the filtrate was added spiroindenylpiperidine hydrochloride(68 mg, 0.307 mmol), diisopropylethylamine (42 μL, 0.307 mmol), crushed4 Å molecular sieves (50 mg) and the resulting mixture was treated withsodium triacetoxyborohydride (325 g, 1.54 mmol). After stirring atambient temperature for 24 hours, the sieves were filtered off, thefiltrate was washed with a saturated solution of sodium bicarbonate(1×10 mL), water (3×5 mL) and brine (1×10 mL). After drying (anhydroussodium sulfate) the solvent was evaporated to dryness under reducedpressure to leave 200 mg of crude product, which was further purified bypreparative TLC (eluant: 5% methanol/95% ethyl acetate) to give 137 mg(68%) of the pure final product. ¹H NMR (500 MHz, CDCl₃): 7.80 (s, 3H),7.32 (d, J=7.3 Hz, 1H), 7.27-7.23 (m, 1H), 7.20-7.15 (m, 2H), 6.79 (d,J=5.7, 11), 6.75 (d, J=5.7 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H), 2.99 (br d,J=12.1 Hz, 2H), 2.58 (t, J=6.6 Hz, 2H), 2.48 (t, J=6.7 Hz, 211), 2.37(br t, J=12.0 Hz. 2H), 2.04 (br t, J=11.8 Hz, 21), 1.96 (t, J=6.7 Hz,2H), 1.34 (br d, 12.3 Hz, 2H). LC-MS: for C₂₆H₂₆N₂OF₆ [M+H] calculated496.19, found 497.

Intermediate 15

Step A

Lithium diisopropyl amide (LDA) was freshly prepared by treating asolution of diisopropylamine (3.75 ml, 26.8 mmol) in dry THF (10 ml)under nitrogen cooled to −78° C. with 2.5 M n-butyl lithium (10.72 ml,26.79 mmol) added slowly via syringe. To this solution was added methylhydrocinnamate (4.0 g, 24 mmol) in dry TB (50 ml) via syringe dropwiseover a 30 minute period. The resulting solution was stirred at −78° C.for 1 hour; then allyl bromide(2.74 ml, 31.7 mmol) was added via syringeand the reaction mixture was stirred overnight allowing to warm to roomtemperature. The reaction was quenched with a saturated solution ofammonium chloride (100 ml) and the resulting mixture was poured into aseparatory funnel. The organic layer was separated, washed with brine(1×100 mL), dried with anhydrous sodium sulfate and the solvent wasevaporated. The crude residue was purified by MPLC (eluant 15% ethylacetate/hexane) to yield 4.96 g (98%) of the racemic desired product.Step B:

A solution of material from Step A, Intermediate 15 (2.86 g, 14.0 mmol)in dichloromethane (50 mL) was cooled to −78° C. and a stream of ozonewas passed through until the permanent blue color indicated completeconsumption of the olefin. The excess ozone was purged with a stream ofnitrogen and allowed to warm up to ambient temperature. Methyl sulfide(10.3 ml, 140 mmol) was added to the solution to reduce the ozonide tothe aldehyde. The solvent was evaporated under reduced pressure and thenazeotroped with toluene to help remove most of the methyl sulfide.

The residue was then taken up into a solution ofdichloromethane/methanol (1:1 solution, 80 ml) and treated withtrimethyl orthoformate (7.66 ml, 70.0 mmol) and a catalytic amount ofp-toluenesulfonic acid (266 mg, 1.40 mmol). After stirring overnight,the solvent was evaporated under reduced pressure and the residue wasthen dissolved in ethyl acetate (300 ml). The solution was washed withsaturated sodium bicarbonate (2×100 ml), water (75 ml), brine (100 ml),dried over anhydrous sodium sulfate, filtered, and the solventevaporated as before. Purification by MPLC (eluant: 15% ethylacetate/hexane) afforded 2.16 g (62%) of the desired product.

¹H NMR (500 M, CDCl₃): 7.35-7.28 (m, 2H), 7.25-7.08 (m, 3H), 4.42 (t,J=6.6 Hz, 11) 3.62 (s, 3H), 3.31 (s, 3E), 3.26 (s, 3H), 2.98(app q,J=6.4 Hz, 1H), 2.85-2.73 (m, 2H), 2.09-1.99 (m, 1H), 1.80-1.72 (m, 1H).Step C:

A solution of material from Step B, Intermediate 15 (2.16 g, 8.56 mmol)in THF/methanol/water (1:1:1 solution, 60 ml) was treated with lithiumhydroxide monohydrate (1.80 g, 42.8 mmol) and the resulting solution wasstirred at room temperature for 48 hours. The organic solvents wereevaporated under reduced pressure to leave the aqueous layer containingthe product. The aqueous layer was diluted with ethyl acetate (75 ml)and the pH adjusted to approximately 6 with 2N HCl solution. The organiclayer was separated and the aqueous was extracted with ethyl acetate(3×75 ml). The organics were combined, washed with brine (1×100 ml),dried over anhydrous sodium sulfate, filtered, and the solventevaporated under reduced pressure. The residue was azeotroped withtoluene to remove any acetic acid, formed by the ethyl acetateextraction, and water to yield 1.77 g (87%) of the crude product whichwas used without further purification. ¹H NMR (500 MHz, CDCl₃):7.35-7.28 (m, 2H), 7.25-7.08 (m, 3H), 4.42 (t, 3=6.6 Hz, 1H), 3.31 (s,3H), 3.26 (s, 3H), 2.98 (dd, J=6.4, 10.6 Hz, 1H), 2.85-2.73 (m, 2H),2.05-1.97 (m, 1H), 1.81-1.75 (m, 1H).

Step A:

4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin was swelled indichloroethane (20 ml) for 30 minutes after which the sovent was drain.A fresh cocktail of 5% trimethyl orthoformate in dichloroethane (15 ml)was added to the resin. To this suspension was then added3,5-bis(trifluoromethyl)benzyl amine (1.00 g, 4.05 mmol) and sodiumtriacetoxyborohydride (858 mg, 4.05 mmol) and the resulting mixture wasspun on a mechanical rotary for 15 hours, releasing pressure every 15minutes for the first 5 hours. The solvent was drained and the resinbeads washed with methanol (2×10 ml), dichloroethane (3×10 ml), dimethylformamide (5×10 ml), dichloromethane (3×10 ml) and ether (3×10 ml). Theresin was first dried by flowing nitrogen through the container; thenunder high vacuum overnight.Step B:

The prepared resin from Step A, Intermediate 16 (50 mg, 0.027 mmol) wasswelled in dichloromethane (2 ml) for 15 minutes after which the solventwas drained. HOAt (19 mg, 0.14 mmol), Intermediate 15 (33 mg, 0.14mmol), dry dichloromethane (2 ml) were added to the pre-swelled resinand was shaken for 2 minutes. To this mixture was then added DICI (22μl, 0.14 mmol) and the resulting mixture was spun on the mechanicalrotary overnight. The solvent was drained and the resin beads washedwith methanol (2×10 ml), dichloroethane (3×10 ml), dimethyl formamide(5×10 ml), dichloromethane (3×10 ml) and ether (3×10 ml). The resin wasfirst dried by flowing nitrogen through the container; then under highvacuum overnight.Step C

The prepared resin from Step B, Intermediate 16 (50 mg, 0.027 mmol) wastreated with a pre-mixed cocktail of 1% trifluoroacetic acid indichloromethane (2 ml) for 2 hours. The solvent was drained and theresin beads washed with dichloromethane (10×1 ml), 1% N,N-diisopropylethyl amine in dichloromethane (5×1 ml) and then again withdichloromethane (6×1 ml). The resin was then dried by flowing nitrogenthrough the container; followed by further drying under high vacuum.

EXAMPLE 18

The prepared resin (Intermediate 16, 50 mg, 0.027 mmol) was swelled indichloroethane (2 ml) for 15 minutes after which the solvent was drain.A fresh cocktail of 5% trimethyl orthoformate in dichloroethane (2 ml)was added to the resin. To this suspension was then addedspiroindenylpiperidine hydrochloride (30 mg, 0.14 mmol),diisopropylethylamine (24 μL, 0.14 mmol), and sodiumtriacetoxyborohydride (57 g, 0.27 mmol) and the resulting mixture wasspun on a mechanical rotary for 15 hours, releasing pressure every 15minutes for the first 3 hours. The solvent was drained and the resinbeads washed with methanol (3×2 ml), dichloroethane (5×2 ml), dimethylformamide (5×2 ml), dichloromethane (10×2 ml). The resin was thenimmediately treated with a pre-mixed cocktail of 25% trifluoroaceticacid in dichloromethane (2 ml) for 2 hours. The beads became dark redafter treatment with the acidic solution. The solvent was collectedalong with the dichloromethane washings (3×2 ml) and concentrated todryness under reduced pressure to afford 2.5 mg (31%) of the desiredfinal product with an HPLC purity analysis of 91%.

¹H NMR (500 MHz, CD₃OD): 7.87 (s, 1H), 7.78 (s, 21), 7.36 (d, J=7.3 Hz,1H), 7.28-7.22 (m, 1H), 7.18-7.10 (m, 2H), 6.99 (br s, 11), 6.90 (br d,J=5.5 Hz, 1H), 4.55 (d, J=15.1 Hz, 1H), 4.28 (d, J=15.1 Hz, 111),3.74-3.66 (m, 1H), 3.30(p, J=1.6 Hz, 1H), 3.36-3.26 (m, J=3H) 3.18-3.12(m, 1H), 2.95 (dd, J=9.1, 13.3 Hz, 1H), 2.85 (dd, 3=6.1, 13.2 Hz, 1H),2.76-2.70 (m, 1H), 2.50-2.40 (m, 1H), 2.22-2.12 (m, 1H), 2.08-1.97 (m,1H), 1.52 (br d, J=14.0 Hz, 2H). LC-MS: for C₃₃H₃₂N₂OF₆ [M+H] calculated586.24, found 587.

Additional compounds were prepared in a similar fashion as Example 18,with the modification of replacing the benzyl intermediate with otheraryl and alkyl groups. TABLE 7

FW: formula/found Example R (M + H) 18-1

C₃₀H₃₂N₂OF₆ 623 18-2

C₃₀H₃₀N₂OF₆ 593 18-3

C₃₂H₃₀N₂OF₆ 573

Additional compounds were prepared in a similar fashion as Example 18above, with the modification of replacing bis3,5-(trifluoromethyl)benzyl amine with a varied array of substitutedbenzyl amines. TABLE 8

FW: formula/found Example R (M + H) 18-4

C₃₀H₃₂N₂O 437 18-5

C₃₀H₃₀N₂OCl₂ 506, 508 18-6

C₃₁H₃₂N₂OCl₂ 506, 508 18-7

C₃₁H₃₁N₂OF₃ 505 18-8

C₃₁H₃₄N₂O₂ 467 18-9

C₃₄H₃₄N₂O 487

Intermediate 17

Step A:

To a solution of 4-pentenoic acid (2.83 g, 28.2 mmol) andN,N-diisopropyl ethylamine (4.89 ml, 28.2 mmol) in dry THF (20 ml) undernitrogen cooled to 0° C. was added dropwise via syringe pivolylchloride(3.48 ml, 28.2 mmol) and the resulting solution stirred for 1 hour atthe monitored temperature. A white precipitate forms quickly after theaddition of the pivolylchloride.

In a second flask, a solution of (S)-(−)-4-benzyl-2-oxazolidine (Evan'sauxiliary, 5.0 g, 28 mmol) in dry THF (20 ml) under nitrogen cooled to−78° C. was treated dropwise with 1.6M n-butyl lithium (18.51 ml, 29.63mmol) and the resulting solution also stirred for 1 hour at themonitored temperature.

After one hour of stirring, the two solutions were combined bycannulating the 4-pentenoic acid solution into the Evan's auxiliarysolution. The resulting mixture was stirred overnight allowing to warmto ambient temperature. The reaction was quenched with water (80 ml) anddiluted with ethyl acetate (160 ml). The organic layer was extracted andwashed with water (40 ml), brine (40 ml), dried over anhydrous sodiumsulfate, filtered, and the solvent evaporated under reduced pressure.The residue was purified by MPLC (eluant: 30% ethyl acetate/hexane) togive 5.34 g (73%) of the desired product.Step B:

A solution of material from Step A, Intermediate 17 (4.0 g, 15 mmol) indichloromethane (50 mL) was cooled to −78° C. and a stream of ozone waspassed through until the permanent blue color indicated completeconsumption of the olefin. The excess ozone was purged with a stream ofnitrogen and allowed to warm up to ambient temperature. Methyl sulfide(11.5 ml, 154 mmol) was added to the solution to reduce the ozonide tothe aldehyde. The solvent was evaporated under reduced pressure and thenazeotroped with toluene to help remove most of the methyl sulfide.

The residue was then taken up into a solution ofdichloromethane/methanol (1:1 solution, 100 ml) and treated withtrimethyl orthoformate (8.43 ml, 77.2 mmol) and a catalytic amount ofp-toluenesulfonic acid (295 mg, 1.55 mmol). After stirring overnight,the solvent was evaporated under reduced pressure and the residue wasthen dissolved in ethyl acetate (300 ml). The solution was washed withsaturated sodium bicarbonate (2×100 ml), water (75 ml), brine (100 ml),dried over anhydrous sodium sulfate, filtered, and the solventevaporated as before. Purification by MPLC (eluant: 50% ethylacetate/hexane) afforded 4.33 g (92%) of the desired product.

¹H NMR (400 MB, CDCl₃): 7.40-7.24 (m, 3H), 7.22-7.18 (m, 2H), 4.76-4.62(m, 1H), 4.51 (t, J=5.7 Hz, 111), 4.24-4.08 (m, 3H) 3.32 (s, 3H), 3.29(s, 3H), 3.27 (dd, J=3.4, 13.5 Hz, 1H), 3.05-2.90 (m, 2H), 2.78 (dd,J=9.6, 13.5 Hz, 1H), 2.06-2.00 (m, 2H).Step C:

Lithium diisopropyl amide (LDA) was freshly prepared by treating asolution of diisopropylamine (280 μl, 2.0 mmol) in dry THF (4 ml) undernitrogen cooled to −78° C. with 2.5 M n-butyl lithium (791 μl, 2.00mmol) added slowly via syringe. To this solution was added product fromStep B, Intermediate 17 (520 mg, 2.00 mmol) in dry THF (16 ml) viasyringe dropwise over a 15 minute period. The resulting solution wasstirred at −780C for 1 hour; then methyl iodide(162 μl, 2.60 mmol) wasadded via syringe and the reaction mixture was stirred overnightallowing it to warm to room temperature. The reaction was quenched witha saturated solution of ammonium chloride (25 ml) and the resultingmixture was poured into a separatory funnel. The organic layer wasseparated, washed with brine (1×15 mL), dried with anhydrous sodiumsulfate and the solvent was evaporated. The crude residue was purifiedby MPLC (eluant 40% ethyl acetate/hexane) to yield 422 mg (77%) of thedesired isomerically pure 2-(R)-methyl substituted product.

¹H NMR (500 MHz, CDCl₃): 7.40-7.24 (m, 3H), 7.22-7.18 (m, 2H), 4.72-4.67(m, 1H), 4.45 (t, J=5.7 Hz, 1H), 4.24-4.17 (m, 3H), 3.95-3.90 (m, 1H),3.32 (s, 3H), 3.29 (s, 3H), 3.27 (dd, J=3.4, 13.5 Hz, 1H), 2.79 (dd,J=9.5, 13.4 Hz, 1H), 2.24-2.16 (m, 1H), 1.73 (dt, J=5.2, 13.8 Hz, 1H),1.27 (d, J=7.1 Hz, 3H).Step D:

The product from Step C, Intermediate 17 (400 mg, 1.20 mmol) was treatedwith solution of 90% trifluoroacetic acid/water (8 ml) for 10 minutes.The reaction mixture was diluted with water (12 mL) and extracted withether (3×10 ml). The organic layers were combined, washed with saturatedsodium bicarbonate (3×10 mL), brine (1×10 mL), dried over anhydroussodium sulfate and the solvent was evaporated in vacuo to yield 361 mg(100%) of the crude product.

A solution of the above crude product (361 mg, 1.20 mmol),spiroindenylpiperidine hydrochloride (266 mg, 1.20 mmol),diisopropylethylamine (205 μL, 1.20 mmol) and crushed molecular sieves(4A, 150 mg) in dichloroethane (20 mL) was treated with sodiumtriacetoxyborohydride (1.3 g, 6.0 mmol) and stirred at room temperatureovernight. The sieves were filtered off (plug of Celite), washed withdichloromethane and the combined organic washings were extracted with asaturated solution of sodium bicarbonate (1×20 mL), brine (1×20 mL) anddried over anhydrous sodium sulfate. Solvent was evaporated to drynessand the residue was purified by preparative TLC (eluent: 5% methanol/95%ethyl acetate) to yield 245 mg (46%) of the desired product. ¹H NMR (500MHz, CDCl₃): 7.38-7.14 (m, 91), 6.84 (d, J=5.7 Hz, 1H), 6.75 (d, J=5.5Hz, 1H), 4.81-4.75 (m, 1H), 4.30-4.21 (m, 2H) 3.93-3.86 (m, 1H), 3.35(dd, J=3.4, 13.3 Hz, 1H), 3.00 (br d, J=11.2 Hz, 2H) 2.82 (dd, J=9.6,13.3 Hz, 1H), 2.52 (br t, J=7.3 Hz, 2H), 2.38-2.26 (m, 2H), 2.17-2.08(m, 3H), 1.73-1.64 (m, 2H), 1.36 (br d, J=13.3 Hz, 2H), 1.29 (d, J=7.1Hz, 3H). LC-MS: for C₂₈H₃₂N₂O₃ [M+H] calculated 444.24, found 445.Step E

A solution of compound from Step D, Intermediate 17 (100 mg, 0.113 mmol)in THF (1 ml) was added via syringe to a prepared solution of hydrogenperoxide (94 μl, 0.90 mmol), lithium hydroxide monohydrate (18 mg, 0.45mmol), water (0.667 ml) and THF (2 ml) cooled to 0° C. by ice/waterbath. The resulting mixture turned cloudy after 10 minutes stirring at0° C., then turned clear after an additional hour of stirring. Thereaction was washed with ether (2×5 ml) and then the pH of the aqueouslayer was adjusted to 7 by careful addition of 1N HCl. The product wasextracted from the neutral aqueous layer with dichloromethane (6×5 ml).The organics were combined, dried over anhydrous sodium sulfate,filtered, and the solvent evaporated under reduced pressure to give 20mg (32%) of the desired crude product as a clear oil.

EXAMPLE 19

A mixture of the acid (Intermediate 17, 15 mg, 0.067 mmol),3,5-bis(trifluoromethyl)benzylamine hydrochloride (15 mg, 0.067 mmol),HOAt (8 mg, 0.07 mmol), N,N-diisopropyl ethylamine (9 μl, 0.07 mmol) indichloromethane (3 mL) was treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 21mg, 0.11 mmol) and stirred at room temperature overnight. The reactionmixture was diluted with dichloromethane (5 mL), washed with water (2×5mL), brine (1×5 mL), dried over anhydrous sodium sulfate and the solventwas evaporated. Purification was done by preparative TLC (eluant: 5%methanol/95% ethyl acetate) to yield 14.1 mg (40%) of the desired finalproduct. ¹H NMR (500 MHz, CDCl₃): 7.80 (s, 2H), 7.59 (s, 1H), 7.34-7.18(m, 4H), 6.79 (d, J=5.7 Hz, 1H), 6.75 (d, J=5.5 Hz, 1H), 4.68-4.56 (m,2H), 3.15 (br d, J=13.5 Hz, 2H) 2.79 (br d, J=13.5 Hz, 1H), 2.52 (br t,J=7.3 Hz, 2H), 2.60-2.52 (m, 2H), 2.47-2.42 (m, 1H), 2.36 (dt, J=3.0,13.4 Hz, 1H) 2.27 (dt, 3.1, 13.4 Hz, 1H), 2.08-2.02 (m, 1H), 1.96 (appbr dt, J=2.8, 13.5 Hz, 1H), 1.90-1.75 (m, 2H), 1.40-1.29 (m, 2H) 1.29(d, J=7.1 Hz, 3H). LC-MS: for C₂₇H₂₈N₂OF₆ [M+H) calculated 510.21, found511.

Additional compounds were prepared in a similar fashion as Example 19above, with the modification of replacing the methyl with differentalkyl groups. TABLE 9

FW: formula/found Example R (M + H) 19-1

C₂₉H₃₂N₂OF₆ 539 19-2

C₂₉H₃₀N₂OF₆ 537

Intermediate 18

Step A

A solution containing cyclopropaneacetic acid (10.2 g, 102 mmol) anddiisopropylethylamine (31.5 mL, 224 mmol) was cooled to −78° C. andbutyl lithium (1.6M, 140 mL) was added drop-wise. The white suspensionwas allowed to warm up to app. +15° C., than it was heated to 50° C. for30 minutes. The reaction mixture was cooled again to −10° C. and treatedwith 2,2-dimethyxy-1-bromoethane (24.1 mL, 204 mmol). The cooling bathwas removed, and the reaction mixture was allowed to warm up to ambienttemperature. The reaction was completed by heating to +50° C. for 30minutes. It was standing at room temperature overnight. The reactionmixture was diluted with water, and the non-acidic components wereextracted with diethyl ether. The pH of the aqueous solution was set toacidic (20 g of citric acid) and extracted with diethyl ether again. Thecombined (acidic) extracts were dried with anhydrous magnesium sulfateand evaporated to dryness. The crude product was further purified bydistillation, which yielded 4.7447 g of recovered startingcyclopropanecacetic acid (b.p.: 75° C./0.3 mmHg) and 6.1538 g (32%) ofthe desired product, b.p.: 110° C./0.3 mmHg. ¹H NMR (CDCl₃): 4.51 (t,J=5.72 Hz, 1H), 3.32 (s, 6H), 2.14 (ddd, J=14.7, 9.2, 6.0 Hz, 1H), 1.90(dt, J=14.0, 5.5 Hz, 1H), 1.72 (ddd, J=9.6, 9.6, 5.3 Hz, 1H), 0.92 (m,1H), 0.56 (m, 2H), 0.38 (m, 1H), 0.20 (m, 1H).Step B

A solution of the acid from previous step (1.40 g, 7.44 mmol) in dryanhydrous tetrahydrofuran (30 mL), diisopropylethylamine (1.26 mL, 7.44mmol) at 0° C. was treated with pivaloyl chloride (896 mg, 7.44 mmol)and stirred at this temperature for 1 hr. In a separate flask, asolution of 5-(5R)-benzyloxazolidin-2-one (1.32 g, 7.44 mmol) in drytetrahydrofuran (30 mL) was treated at −78° C. with n-butyl lithium(3.12 mL, 1.6 M in hexanes, 7.81 mmol) and stirred at this temperaturefor 1 hr. The solution of the lithium salt was transferred into theflask containing the activated acid at 0° C., and the solution wasstirred at room temperature overnight. The solvent was removed in vacuo,the residue was picked up into water (50 mL) and extracted with ethylacetate (4×50 mL). The combined organic extracts were washed with brine,filtered and the solvent was distilled off on Rotavap. Flashchromatography (Lobar, Lichroprep Si60, 40-63 μm) using ethylacetate/hexane (3:7) eluent gave 828 mg, (32%) of the higher elutingdiastereoisomer and 277.6 mg (11%) of the lower eluting diastereoisomer.The absolute stereochemistry contained within the side-chain (C2) wasoptimal for maximum pharmacological activity.

Hi-R_(f)-Diastereoisomer: ¹H NMR (CDCl₃): 7.34 (m, 2H), 7.26 (m, 3H),4.68 (m, 1H), 4.55 (dd, J=7.1, 4.1 Hz, 1H), 4.15 (m, 2H), 3.44 (dd,J=12.7, 2.7 Hz, 1H), 3.34 (m, 1H), 3.31 (s, 3H), 3.29 (s, 3H), 2.64 (dd,J=13.3, 10.6 Hz, 1H), 2.35 (J=14.0, 9.6, 7.3 Hz, 1H), 1.97 (dt, J 14.0,4.1 Hz,), 1.06 (m, 1H), 0.58 (m, 1M), 0.46 (m, 1H), 0.33 (m, 1H), 0.25(m, 1H).

Lo-R_(f)-Diastereoisomer: ¹H NMR (CDCl₃): 7.24 to 7.36 (bm, 5H), 4.75(m, 1H), 4.47 (dd, J=7.1, 4.4 Hz, 1H), 4.18 (m, 2H), 3.37 (m, 1H), 3.29(m, 1H), 3.28 (s, 3H), 3.26 (s, 3H), 2.85 (dd, J=13.5, 9.4 Hz, 1H), 2.33(ddd, J=14.0, 9.9, 7.3 Hz, 1H), 1.94 (dt, J=14.0, 4.4 Hz, 1H), 1.08 (m,1H), 0.61 (m, 1H), 0.50 (m, 2H), 0.29 (m, 1H).Step C

The more polar acetal from previous step (277.0 mg, 0.7973 mmol,Lo-R_(f)-Diastereoisomer) was briefly treated with 90% trifluoroaceticacid, diluted with diethyl ether and washed with saturated solution ofsodium bicarbonate. The organic phase was dried with anhydrous magnesiumsulfate and evaporated to dryness to yield 265 mg (96%) of therespective aldehyde.

¹H NMR (CDCl₃): 9.76 (s, 1H), 7.36 to 7.24 (bm, 5H), 4.76 (m, 1H), 4.31(t, J=8.5 Hz, 1H), 4.20 (dd, J=8.9, 3.0 Hz, 1H), 3.75 (ddd, J=13.7,9.8,3.9 Hz, 1H), 3.26 (dd, J=13.5, 3.4 Hz, 1H), 3.19 (dd, J=18.5, 10.3 Hz,1H), 2.87 (dd, J=13.5, 9.2 Hz, 1H), 2.83 (ddd, J=18.5, 4.1, 0.7 Hz, 1H),1.02 (m, 1H), 0.68 (m, 1H), 0.62 (m, 1H), 0.54 (m, 1H), 0.27 (m, 1H).Step D

A solution of the aldehyde from previous step (265 mg, 0.763 mmol),methyspiroindene, hydrochloride (188 mg, 0.797 mmol),diisopropylethylamine (135 μL, 0.797 mmol) in dichloroethane (10 mL) wastreated with sodium triacetoxyborohydride (500 mg, 2.359 mmol) andstirred at room temperature overnight. The reaction mixture was dilutedwith dichloromethane (50 mL), washed with saturated solution of sodiumbicarbonate (1×30 mL), water (1×30 mL) and brine (1×30 mL). It was driedwith anhydrous sodium sulfate, filtered and the solvent was removed invacuo to leave 330.7 mg (86%) of product, pure enough to perform thesubsequent step. ¹H NMR (CDCl₃): 7.40 to 7.12 (bm, 9 H), 6.80 (d, J=m5.7Hz, 1H), 6.65 (d, J=5.7 Hz, 1H), 4.84 (m, 1H), 4.27 (t, J=8.92 Hz, 1H),4.22 (dd, 3=8.9, 3.4 Hz, 1H), 3.36 (m, 2H), 2.86 (dd, J=13.5, 9.4 Hz,1H), 2.24 (m, 4H), 1.30 (m, 1H), 1.1 (m, 1H), 0.64 (m, 1H), 0.54 (m,1H), 0.47 (m, 1H), 0.32 (m, 4H).Step E

A solution of the imide from previous step (80 mg, 0.17 mmol) in THF(2.0 mL) was cooled to 0° C. and treated with 75 μL of hydrogen peroxide(30%, aqueous solution, app. 1.1 mmol) followed by a solution of lithiumhydroxide (14 mg) in water (1.0 mL). This mixture was stirred at 0° C.for 10 minutes and the reaction was quenched with saturated solution ofsodium sulfite (520 μL). Most of the THF was distilled off on Rotavap,the residue was diluted with water (2 mL) and extracted withdichloromethane (3×2 mL) to remove the non-acidic reaction components.pH was adjusted to 7.0 (1N HCl) and the product was extracted withchloroform (6×4 mL). The combined extracts were dried with anhydroussodium sulfate and evaporated to dryness to leave 40.2 mg (75%) of thedesired acid. ¹H NMR (CDCl₃): 7.35 (bd, J=6.9 Hz, 1H), 7.31 (bd, J=6.9Hz, 1H), 7.27 to 7.20 (bm, 2H), 6.88 (d, J=5.7 Hz, 1H), 6.61 (d, J=5.7Hz, 1H), 3.44 (bd, J=11.7 Hz, 1H), 3.32 (dd, J=12.1 Hz, 2.3 Hz, 1H),3.13 (m, 1H), 2.87 (m, 1H), 2.71 (dt, J=13.5, 2.5 Hz, 1H), 2.63 (m, 1H),2.54 (dt, J=13.7, 3.9 Hz, 1H), 2.41 (t, J=12.1 Hz, 1H), 2.15 (m 1H),2.00 (m, 1H), 1.84 (m, 1H), 1.41 (dt, J=14.0, 2.5 Hz, 1H), 1.05 (m, 1H),0.68 (m 1H), 0.58 (m, 1H), 0.51 (m, 1H), 0.36 (d, J=6.63 Hz, 3M), 0.18(m, 1H).

Intermediate 19

Was synthesized from the corresponding chiral acid (650 mg, 4.6368 mmol,obtained by allylation ofN-cyclopropanylacetyl-5-(S)-benzyloxazolidin-2-one and cleavage of theauxiliary group as described for Intermediate 18) followed by amideformation with 3,5-bistrifluoromethylbenzylamine hydrochloride in asimilar fashion as described under Intermediate 1, Step B. ¹H NMR(CDCl₃): 7.79 (s, 1H), 7.74 (s, 2H), 6.20 (bs, 1H), 5.81 (m, 1H), 5.11(bdd, J=17.2, 1.6 Hz, 1H), 5.04 (bd, J=10.1 Hz, 1H), 4.62 (m, 2H), 2.56(m, 2H), 1.53 (ddd, J=9.8, 8.2, 5.5 Hz, 1H), 1.01 (m, 1H), 0.65 (m, 2H),0.25 (m, 2H).

EXAMPLE 20

Procedure A

A solution of Intermediate 18 (145 mg, 0.446 mmol),3,5-bistrifluoromethylbenzylamine hydrochloride (125 mg, 0.446 mmol),1-hydroxy-7-azabenzotriazole (60 mg, 0.45 mmol), diisopropylethylamine(78 μL, 0.45 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (EDC, 130 mg, 0.668 mmol) was stirred at room temperatureovernight. Dichloromethane (30 mL) was added and the reaction mixturewas extracted with saturated solution of sodium bicarbonate (1×30 mL).The aqueous phase was extracted with dichloromethane (2×20 mL), theorganic phases were combined, dried and evaporated to dryness to leave174.7 mg of crude product. This was further purified by preparative TLC(100% ethyl acetate) to give 115.1 mg (47%) of pure product.

Procedure B

A solution of the olefin Intermediate 19 (603 mg, 1.65 mmol) indichloromethane (50 mL) was cooled to −78° C. and a stream of ozone waspassed through until the permanent blue color indicated completeconsumption of the olefin. The excess of ozone was purged with nitrogen,and the solution of the ozonide was allowed to warm up to roomtemperature. The solution was dried with anhydrous magnesium sulfate andfiltered. 3-Methyl-4-spiroindenylpiperidine. hydrochloride (389 mg, 1.65mmol) was added, followed by 4A molecular sieves, diisopropylethylamine(287 μL, 1.65 mmol) and finally sodium triacetoxyborohydride (1.75 g,8.25 mmol). Stirring at room temperature was continued overnight. Thereaction mixture was diluted with dichloromethane (100 mL) and thesieves were filtered off through a plug of Celite. The filtrate wasextracted with saturated solution of sodium bicarbonate (1×50 mL), theaqueous extracts were back-washed with dichloromethane (1×50 mL). Thecombined organic phases were dried with anhydrous sodium sulfate and thesolvent was removed in vacuo. The crude product was purified by flashchromatography (ethyl acetate methanol/95: 5) to yield 533 mg (58%) ofpure product.

¹H NMR (Hydrochloride, CDCl₃): 11.9 (bs, 1H), 8.5 (bs, 1H), 7.86 (bs,2H), 7.75 (s, 1H), 7.47 (m, 1H), 7.35 to 7.25 (bm, 3H), 6.94 (d, J=5.7Hz, 1H), 6.48 (d, J=5.7 Hz, 1H), 4.64 (dd, J=15.6, 5.7 Hz, 1H), 4.54(dd, 15.6, 6.0 Hz, 1H), 3.52 (bd, J=11.7 Hz, 1H), 3.14 (m, 2H), 2.98(bs, 1H), 2.90 m (1H), 2.55 (m, 1H), 2.36 (m, 2H), 2.22 (m, 1H), 1.44(d, J=14.7 Hz, 1H), 1.05 (m, 1H), 0.64 (m, 2H), 0.47 (m, 1H), 0.43 (d,J=6.9 Hz, 3H), 0.25 (m, 1H).

EXAMPLE 21

Example 21 was synthesized according to the procedure described forpreparation of Example 20, except that 4-spiroindenylpiperidine was usedinstead of 3-methyl-4-spiroindenylpiperidine in Step D, Intermediate 18.¹H NMR (CDCl₃): 7.80 (bs, 3H), 7.33 (bd, J=7.3 Hz, 1H), 7.28 to 7.18(bm, 3H), 7.07 (bs, 1H), 6.82 (d, J=5.7 Hz, 1H), 6.75 (d, J=5.7 Hz, 1H),4.65 (m, 2H), 3.02 (bd, J=11.9 Hz, 1H), 2.85 (bd, J=11.9 Hz, 1H), 2.58(m, 1H), 2.50 (m, 1H), 2.37 (dt, J=J=11.1, 2.5 Hz, 1H), 2.27 (dt,J=11.7, 2.1 Hz, 1H), 2.05 (m, 4H), 1.86 (m, 3H), 1.35 (m, 2H), 1.05 (m,1H), 0.66 (m, 2H), 0.27 (m, 2H).

EXAMPLE 22

Example 22 was synthesized according to the procedure described forpreparation of Example 20, except that 4-(4-fluorophenyl)piperidine wasused instead of 3-methyl-4-spiroindenylpiperidine in Step D,Intermediate 18. ¹H NMR (CDCl₃): 7.80 (bs, 1H), 7.77 (bs, 2H), 7.12 (m,2H), 6.98 (m, 2H), 4.633 (m, 2H), 3.03 (bd, J=11.4 Hz, 1H), 2.85 (bd,J=11.4 Hz, 1H), 2.43 (m, 2H), 2.32 (m, 1H), 2.1 to 1.9 (bm, 4H), 1.86 to1.50 (bm, 7H), 1.05 (m, 1H), 0.64 (m, 2H), 0.28 (m, 1H), 0.20 (m, 1H).

EXAMPLE 23

Example 23 was synthesized according to the procedure described forpreparation of Example 20, except that 4-phenylpiperidine was usedinstead of 3-methyl-4-spiroindenylpiperidine in Step D, Intermediate 18.¹H NMR (CDCl₃): 7.79 (bs, 1H), 7.78 (bs, 2H), 7.32 to 7.15 (bm, 5H),4.62 (m, 2H), 3.05 (bd, J=11.4 Hz, 1H), 2.85 (bd, J=11.4 Hz, 1H), 2.50(m, 2H), 2.32 (m, 1H), 2.10 (dt, J=1 2.1, 2.5 Hz, 1H), 2.04 to 1.58 (bm,10H), 1.05 (m, 1H), 0.64 (m, 2H), 0.32 to 0.18 (bm, 2H).

EXAMPLE 24

Example 24 was synthesized according to a procedure analogous to thatdescribed for preparation of Example 20. ¹H NMR (CDCl₃): 7.82 (s, 2H),7.80 (s, 1H), 7.32 to 7.18 (bm, 5H), 6.83 (d, J=5.7 Hz, 1H), 6.62 (d,J=5.7 Hz, 1H), 4.65 (dd, J=6.2, 15.6 Hz, 1H), 4.60 (dd, J=15.6, 6.0 Hz,1H), 3.0 (bd, J=10.8 Hz, 1H), 2.88 (bd, J=11.0 Hz, 1H), 2.54 (bs, 2H),2.45 (m, 1H), 2.32 (m, 2H), 2.22 (m, 1H), 2.02 (m, 3H), 1.89 (m, 2H),1.75 (m, 1H), 1.37 (m, 1H), 1.28 (bd, J=13.5 Hz, 1H), 0.72 (m, 1H), 0.45(m, 2H), 0.32 (d, J=6.6 Hz, 3H), 0.1 (m, 2H).

EXAMPLE 25

Example 25 was synthesized according to a procedure analogous to thatdescribed for preparation of Example 20. ¹H NMR (CDCl₃): 7.78 (s, 3H),7.32 to 7.18 (bm, 4H), 6.82 (d, 3=5.7 Hz, 1H), 6.62 (d, J=5.7 Hz, 1H),4.64 (dd, J=15.8, 6.2 Hz, 1H), 4.58 (dd, J=15.6, 6.2 Hz, 1H), 3.0 (bs,1H), 2.88 (m, 1H), 2.7 to 1.6 (bm, 22H), 1.28 (m, 1H), 0.33 (d, J=6.9Hz, 3H), 0.09, s 1H).

Intermediate 20

Step A

Lithium diisopropyl amide (LDA) was freshly prepared by treating asolution of diisopropylamine (3.24 ml, 23.1 mmol) in dry THF (40 ml)under nitrogen cooled to −78° C. with 2.5 M n-butyl lithium (9.244 ml,23.11 mmol) added slowly via syringe. To this solution was added ethylcyclohexylacetate (3.77 g, 21.0 mmol) in dry THF (60 ml) via syringedropwise over a 30 minute period. The resulting solution was stirred at−78° C. for 1 hour; then allyl bromide(2.37 ml, 27.3 mmol) was added viasyringe and the reaction mixture was stirred overnight allowing to warmto room temperature. The reaction was quenched with a saturated solutionof ammonium chloride (100 ml) and the resulting mixture was poured intoa separatory funnel. The organic layer was separated, washed with brine(1×100 mL), dried with anhydrous sodium sulfate and the solvent wasevaporated. The crude residue was purified by MPLC (eluant 10% ethylacetate/hexane) to yield 4.24 g (99%) of the racemic desired productStep B:

A solution of the compound synthesized in Step A, Intermediate 20 (500mg, 1.68 mmol) in dichloromethane (20 mL) was cooled to −78° C. and astream of ozone was passed through until the permanent blue colorindicated complete consumption of the olefin. The excess ozone waspurged with a stream of nitrogen and allowed to warm up to ambienttemperature. The solution was dried with magnesium sulfate, the dryingagent was filtered off, and to the filtrate was addedspiroindenylpiperidine hydrochloride (419 mg, 1.80 mmol),diisopropylethylamine (328 μL, 1.80 mmol), crushed 4 Å molecular sieves(250 mg) and the resulting mixture was treated with sodiumtriacetoxyborohydride (2.00 g, 9.46 mmol). After stirring at ambienttemperature for 24 hours, the sieves were filtered off, the filtrate waswashed with a saturated solution of sodium bicarbonate (1×100 mL), water(3×50 mL) and brine (1×100 mL). After drying (anhydrous sodium sulfate)the solvent was evaporated to dryness under reduced pressure to leave620 mg of crude product, which was further purified by preparative TLC(eluant: 100% ethyl acetate) to give 456 mg (66%) of the pure desiredproduct. LC-MS for C₂₅H₃₅NO₂ [M+H]⁺ calculated 381.27, found 382.Step C:

A solution of material from Step B, Intermediate 20 (450 mg, 1.12 mmol)in THF/methanol/water (1:1:1 solution, 30 ml) was treated with lithiumhydroxide monohydrate (188 mg, 4.48 mmol) and the resulting solution wasstirred at room temperature for 48 hours. The organic solvents wereevaporated under reduced pressure to leave the aqueous layer containingthe product. The aqueous layer was diluted with ethyl acetate (75 ml)and the pH adjusted to approximately 3 with 6N HCl solution. The organiclayer was separated and the aqueous was extracted with ethyl acetate(3×50 ml). The organics were combined, washed with brine (1×50 ml),dried over anhydrous sodium sulfate, filtered, and the solventevaporated under reduced pressure. The residue was azeotroped withtoluene to remove any acetic acid, formed by the ethyl acetateextraction, and water to yield 397 mg (91%) of the crude product whichwas used without further purification.

EXAMPLE 26

A mixture of the acid (Intermediate 20, 150 mg, 0.387 mmol),3,5-bis(trifluoromethyl)benzylamine hydrochloride (109 mg, 0.387 mmol),HOAt (53 mg, 0.387 mmol), N,N-diisopropyl ethylamine (67 μl, 0.387 mmol)in dichloromethane (10 mL) was treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 148mg, 0.774 mmol) and stirred at room temperature overnight. The reactionmixture was diluted with dichloromethane (20 mL), washed with water(2×20 mL), brine (1×20 mL), dried over anhydrous sodium sulfate and thesolvent was evaporated. Purification was done by preparative TLC(eluant: 60% ethyl acetate/hexane) to yield 173 mg (77%) of the desiredfinal product. LC-MS for C₃₂H₃₆N₂OF₆M+H]⁺ calculated 578.27, found 579.

Intermediate 21

Step A

A suspension of ethyl-3-pyridylacetate (5.0 g, 30 mmol) and platinumoxide (500 mg), in acidic ethanol (200 ml of 1% HCl/EtOH) was placed ona parr shaker and treated with hydrogen at 50 psi for 15 hours. Thereaction was then flushed with nitrogen, the catalyst filtered off (plugof Celite), and the solvent evaporated under reduced pressure to yield5.86 g (100%) of a white solid.

The material was then dissolved in dichloromethane (200 ml) and treatedwith diisopropyl ethylamine (5.25 ml, 30.26 mmol) anddi-tert-butyl-dicarbonate (7.00 g, 31.77 mmol). The resulting mixturewas stirred at room temperature overnight. The solution was washed with1N HCl (100 ml), saturated sodium bicarbonate (100 ml), brine (100 ml),dried over anhydrous sodium sulfate, and the solvent evaporated atreduced pressure to yield 7.5 g (97%) of the crude product as a yellowoil. Purification was done by MPLC (eluant: 10% ethyl acetate/hexane) togive 6.22 g (80%) of the pure desired product.Step B

Lithium diisopropyl amide (LDA) was freshly prepared by treating asolution of diisopropylamine (1.80 ml, 12.8 mmol) in dry THF (20 ml)under nitrogen cooled to −78° C. with 2.5 M n-butyl lithium (5.13 ml,12.8 mmol) added slowly via syringe. To this solution was added theproduct from Step A of Intermediate 21 (3.0 g, 12 mmol) in dry THF (80ml) via syringe dropwise over a 30 minute period. The resulting solutionwas stirred at −78° C. for 1 hour; then allyl bromide(1.32 ml, 12.8mmol) was added via syringe and the reaction mixture was stirredovernight allowing to warm to room temperature. The reaction wasquenched with a saturated solution of ammonium chloride (100 ml) and theresulting mixture was poured into a separatory funnel. The organic layerwas separated, washed with brine (1×100 mL), dried with anhydrous sodiumsulfate and the solvent was evaporated. The crude residue was purifiedby MPLC (eluant 30% ethyl acetate/hexane) to yield 3.22 g (93%) of theracemic desired productStep C:

A solution of the compound synthesized in Step B, Intermediate 21 (1.00g, 3.36 mmol) in dichloromethane (35 mL) was cooled to −78° C. and astream of ozone was passed through until the permanent blue colorindicated complete consumption of the olefin. The excess ozone waspurged with a stream of nitrogen and allowed to warm up to ambienttemperature. The solution was dried with magnesium sulfate, the dryingagent was filtered off, and to the filtrate was addedspiroindenylpiperidine hydrochloride (745 mg, 3.36 mmol),diisopropylethylamine (585 μL, 3.36 mmol), crushed 4 Å molecular sieves(500 mg) and the resulting mixture was treated with sodiumtriacetoxyborohydride (3.56 g, 16.8 mmol). After stirring at ambienttemperature for 24 hours, the sieves were filtered off, the filtrate waswashed with a saturated solution of sodium bicarbonate (1×100 mL), water(3×50 mL) and brine (1×100 mL). After drying (anhydrous sodium sulfate)the solvent was evaporated to dryness under reduced pressure to leave750 mg of crude product, which was further purified by preparative TLC(eluant: 100% ethyl acetate) to give 640 mg (51%) of the pure desiredproduct. ¹H NMR (500 MHz, CDCl₃): 7.37 (d, J=7.3 Hz, 1H), 7.32 (d, J=7.2Hz, 1H), 7.26-7.18 (m, 2H), 6.84 (d, J=5.7, 1H), 6.75 (d, J=5.5 Hz, 1H),4.26-4.17 (m, 1H), 4.06-3.86 (m, 1H), 3.04-2.96 (m, 2H), 2.68 (app t,J=12.4 Hz, 1H), 2.51-2.44 (m, 1H), 2.43-2.37 (m, 1H), 2.31 (br t, J=9.8Hz, 2H), 2.24-2.12 (m, 2H), 2.00-1.88 (m, 2H), 1.82-1.64 (m, 4H), 1.47(br s, 9H), 1.33 (t, J=7.1 Hz, 3H). LC-MS: for C28H40N2O4 [M+H]calculated 468.30, found 469.Step D:

A solution of material from Step C, Intermediate 21 (640 mg, 1.28 mmol)in THF/methanol/water (1:1:1 solution, 30 ml) was treated with lithiumhydroxide monohydrate (214 mg, 5.10 mmol) and the resulting solution wasstirred at room temperature for 48 hours. The organic solvents wereevaporated under reduced pressure to leave the aqueous layer containingthe product. The aqueous layer was diluted with ethyl acetate (75 ml)and the pH adjusted to approximately 3 with 6N HCl solution. The organiclayer was separated and the aqueous was extracted with ethyl acetate(3×50 ml). The organics were combined, washed with brine (1×50 ml),dried over anhydrous sodium sulfate, filtered, and the solventevaporated under reduced pressure. The residue was azeotroped withtoluene to remove any acetic acid, formed by the ethyl acetateextraction, and water to yield 510 mg (80%) of the crude product whichwas used without further purification.Step E:

A mixture of the acid (Step D, Intermediate 21, 360 mg, 0.76 mmol),3,5-bis(trifluoromethyl)benzylamine hydrochloride (212 mg, 0.76 mmol),HOAt (104 mg, 0.76 mmol), N,N-diisopropyl ethylamine (132 μl, 0.76 mmol)in dichloromethane (30 mL) was treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride EDC, 292mg, 1.52 mmol) and stirred at room temperature overnight. The reactionmixture was diluted with dichloromethane (30 mL), washed with water(2×20 mL), brine (1×30 mL), dried over anhydrous sodium sulfate and thesolvent was evaporated. Purification was done by preparative TLC(eluant: 80% ethyl acetate/hexane) to yield 282 mg (53%) of the desiredproduct. LC-MS: for C₃₆H₄₃N₃O₃F₆ [M+H] calculated 679.32, found 680 and579[M+H−Boc].

EXAMPLE 27

A solution of Intermediate 21 (200 mg, 0.317 mmol) in dichloromethane (2ml) was treated with 4N HCl in dioxane (4 ml) and the resulting mixturestirred for 1 hour at room temperature. The solvent was evaporated underreduced pressure to give 197 mg, (99%) of the desired final product.LC-MS for C₃₁H₃₅N₃OF₆ [M+H]⁺ calculated 579.27, found 580.

EXAMPLE 28

A solution of the above synthesized product (EXAMPLE 27, 97.5 mg, 0.162mmol) and triethyl amine (90 μL, 0.65 mmol) in dichloromethane (6 ml)under nitrogen cooled to 0° C. was treated with acetyl chloride (13 μL,0.18 mmol) and the resulting mixture was stirred for 2 hours at 0° C.The mixture was washed with saturated sodium bicarbonate (10 ml), driedover anhydrous sodium sulfate, filtered, and the solvent evaporatedunder reduced pressure. The residue was purified by preparative TLC(eluant: 5% methanol/95% ethyl acetate) to give 92 mg (92%) of thedesired final product. LC-MS for C₃₃H₃₇N₃O₂F₆ [M+H]⁺ calculated 621.28,found 622.

EXAMPLE 29

The title compound was prepared using a synthetic sequence analogous tothat described in Example 28 except that methanesulfonylchloride wasused instead of acetyl chloride. Purification by preparative TLC(eluant: 5% methanol/95% ethyl acetate) gave 94 mg (88%) of the desirefinal product. LC-MS for C₃₂H₃₇N₃O₃F₆S [M+H]⁺ calculated 657.25, found658.

Intermediate 22

Step A

A solution of 3-thienylacetic acid (2.544 g, 17.89 mmol) in drytetrahydrofuran (100 mL) was cooled with an ice/salt bath to −10° C. andthe solution of lithium hexamethylsilazane (40 mL, 1M, in THF) was addeddrop-wise, over a period of 30 minutes. After additional stirring atcold for 30 minutes, the neat 2,2-dimethoxy-1-bromoethane was added viasyringe. The cooling bath was removed and the stirring at roomtemperature was continued for another 3 hrs. The reaction mixture waspoured onto water (100 mL), the non-acidic components were extractedwith diethyl ether (2×50 mL). The pH of the aqueous solution was set to3, (HCl, 2 N) and the crude acid was extracted into diethyl ether (3×50mL). The combined organic extracts were dried with anhydrous sodiumsulfate, and the solvent was evaporated to dryness to leave 1.12 g (27%)of the crude acid, used in the next step without additionalpurification. This racemic acid could be resolved into its respectiveenantiomers using (R)- and/or (S)-α-phenylethylamine salts viacrystallization from ethyl acetate. The acid, which ultimately led tothe more active enantiomer of the racemate shown under Example 30, wasobtained by crystallizations using the salts derived form the (S)-amine.Step B

The solution of the crude acid from Step A (716 mg, 3.11 mmol) and3,5-bistrifluoromethyl benzylamine hydrochloride (870 mg, 3.11 mmol) indichloromethane (10 mL) was treated with 1-hydroxy-7-azabenzotriazole(423 mg, 3.11 mmol), diisopropylethylamine (600 μL, 3.20 mmol) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 895mg, 4.664 mmol) and stirred at room temperature for 1 hr. The reactionmixture was poured onto water (30 mL), extracted with dichloromethane.The combined organic extracts were washed with brine (1×30 mL), driedwith anhydrous magnesium sulfate and the solvent was evaporated todryness under reduced pressure. Flash chromatography (Lobar, LichroprepSi60, 40-63 μm) using ethyl acetate/hexane (4:6) eluent gave 644 mg,(45%, two steps) of pure product. Either of the enantiomers of thestarting acid could be transformed into the enantiomerically pure formof Intermediate 22 in a reaction similar to that performed with theracemic acid, as described under Intermediate 22, Step B.

¹H NMR (CDCl₃, 500 MHz): 7.76 (s, 1H), 7.62 (bs, 2H), 7.36 (dd, J=5.04,2.98 Hz, 1H), 7.18 (bs, 1H), 7.06 (bd, J=5.03 Hz, 1H), 6.04 (t, J=5.5Hz, 1H), 3.34 (s, 3H), 3.28 (s, 3H), 2.53 (ddd, J=14.2, 8.0, 6.2 Hz,1H), 2.03 (ddd, J=14.0, 6.9, 5.5 Hz, 1H).

Intermediate 23

Step A

A solution of 3-thienylacetic acid (4.113 g, 28.92 mmol) in drytetrahydrofurane (20 mL) and cooled to −10° C. with ice/salt bath. Allylbromide (5.5 mL, 7.69 g, 63.6 mmol) was added via syringe and stirringwas continued for another 1 hr at room temperature. The reaction wasquenched with water (100 mL), the non-acidic components were extractedinto diethyl ether. The pH of the aqueous phase was set to 3, and thecrude product was extracted into diethyl ether. The combined organicextracts were washed with brine, dried with anhydrous magnesium sulfate,and evaporated to dryness. The remaining acid (4.08 g, 77%) was used inthe next step without any further purification.Step B

1.67 g, 9.16 mmol) and 3,5-bistrifluoromethyl benzylamine hydrochloride(2.562 g, 9.16 mmol) in dichloromethane (30 mL) was treated with1-hydroxy-7-azabenzotriazole (423 mg, 3.109 mmol), diisopropylethylamine(1.60 mL, 9.18 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (EDC, 2.64 g, 13.7 mmol) and stirred at room temperatureovernight. The reaction mixture was poured onto water (50 mL), extractedwith dichloromethane (3×50 mL). The combined organic extracts werewashed with brine (1×30 mL), dried with anhydrous magnesium sulfate andthe sovent was evaporated to dryness under reduced pressure. The crudeproduct was crystallized from hexane to give 2.3962 g (64%) of pureIntermediate 23.

Intermediate 24

Procedure A

Intermediate 22 (177 mg, 0.389 mmol) was dissolved in trifluoroaceticacid (2.0 mL) and briefly stirred (about 5 minutes) at ambienttemperature. The reaction mixture was diluted with diethyl ether andwashed with water (5×30 mL). The organic layer was dried with anhydrousmagnesium sulfate and evaporated to dryness. The crude product wasco-distilled several times with benzene (to remove remainingtrifluoroacetic acid) and used in the subsequent step immediately.

The respective chiral form Intermediate-24 was obtained in an analogousreaction, except that the respective chiral form of Intermediate 22 wasused as starting material.

Procedure B

The solution of Intermediate 23 (472 mg, 1.16 mmol) and osmium tetroxide(36 mg, 0.14 mmol) in ethanol (10 mL) was treated with a solution ofsodium periodate (620 mg, 2.90 mmol) in water (6 mL). The reactionmixture was stirred at room temperature for 30 minutes and the ethanolwas distilled off under reduced pressure. The remaining aqueoussuspension was extracted with ethyl acetate (3×30 mL), dried withanhydrous sodium sulfate, and evaporated to dryness to yield 362 mg ofcrude product, containing about 30% (HPLC, ¹H NMR) of the desiredaldehyde. This was used immediately in the next step.

A solution of the Intermediate 24 (56 mg, 0.18 mmol) and4-spiroindenylpiperidine hydrochloride (40.3 mg, 0.182 mmol) in drydichloroethane (5 mL) was treated with diisopropylethylamine (40 μL,0.22 mmol) and to this mixture, sodium triacetoxyborohydride (193 mg,5.0 mmol) were added. The reaction was allowed to proceed overnight. Itwas quenched with saturated solution of sodium bicarbonate (20 mL), andthe product was extracted with dichloromethane (3×30 mL). The combinedorganic layers were dried with anhydrous sodium sulfate and evaporatedto dryness (78 mg). The crude product was further purified bypreparative TLC using ethyl acetate/hexane (1:1) as eluent to obtain 28mg, 27%) of pure product. ¹H NMR (CDCl₃, 500 MHz): 7.77 (s, 1H), 7.67(s, 2H), 7.38 (dd, J=5.0, 3.0 Hz, 1H), 7.34 (bt, J=7.8 Hz, 2H), 7.23 (m,3H), 7.10 (dd, J=5.0, 1.4 Hz, 1H), 6.83, (d, J=5.5 Hz, 1H), 6.76 (d,J=5.7 Hz, 1H), 6.62 (bs, 1H), 4.60 (dd, J=15.6 Hz, 1H), 4.54 (dd,J=15.8, 6.2 Hz, 1H), 3.90 (t, J=7.55 Hz, 1H), 3.2 (bd, J=11.4 Hz, 1H),2.96 (bd, =11.4 Hz, 1H), 2.42 (m, 6H), 2,12 (m, 4H).

EXAMPLE 31

was synthesized starting from the chiral form of Intermediate 24 and4-spiroindenylpiperidine according to the procedure described in Example30.

EXAMPLE 32

was synthesized starting from the chiral form of Intermediate 24 and4-phenylpiperidine according to the procedure described in Example 30.¹H NMR (CDCl₃, 500 MHz): 7.78 (s, 1H), 7.66 (bs, 2H), 7.35 (m, 3H), 7.20(m, 3H), 7.08 (d, J=5.0 Hz, 11), 6.78 (bs, 1H), 4.55 (m, 2H), 3.85 (m,1H), 3.05 (d, J=11.2 Hz, 1H), 2.95 (d, J=11.2 Hz, 1H), 2.52 (m, 1H),2.38 (m, 3H), 2.05 (m, 3H), 1.85, (m, 2H), 1.72 (m, 2H).

EXAMPLE 33

was synthesized starting from the chiral form of Intermediate 24 and4-phenylpiperidine according to the procedure described in Example 30.

Intermediate 25

Step A

A solution of enantiomerically pure 4,4-dimethoxy-2-(thien-3-yl)butyricacid, synthesized according to the Procedure A, Intermediate 22 (640 mg,2.6196 mmol) in diethyl ether was treated with an etheral solution ofdiazomethane, added in excess. As soon as effervescence subsided, theexcess diazomethane was purged with a stream of nitrogen, and thesolvent was evaporated under reduced pressure. ¹H NMR (CDCl₃, 500 MHz):7.28 (dd, J=5.0, 3.2, 1H), 7.15 (dd, J=2.8, 1.0 Hz, 1H), 7.06 (dd,J=5.0, 1.4 Hz, 1H), 4.28 (dd, J=6.4, 5.0 Hz, 1H), 3.88 (dd, J=8.5, 7.1Hz, 1H), 3.69 (s, 3H), 3.33 (s, 1H), 3.0 (s, 3H), 2.41 (ddd, J=14.9,8.5, 6.6 Hz, 1H), 2.03 (ddd, J=14.0, 6.9, 5.0 Hz, 1H),Step B

The acetal, synthesis of which was described under Step A (210 mg, 0.860mmol), was dissolved in trifluoroacetic acid, and after 3 minutesdiluted with ether. The organic solution was washed with water (1×30mL), saturated aqueous solution of sodium bicarbonate (3×20 mL), water(1×30 mL) and brine (1×30 mL). The solvent was evaporated to dryness toleave behind 171.6 mg (100%) of the aldehyde, pure enough to be used innext reaction step. ¹H NMR (CDCl₃, 500 MHz): 9.80 (s, 1H), 7.32 (dd,J=5.1, 3.2 Hz, 1H), 7.14 (m, 1H), 7.04 (dd, J=5.1, 1.1 Hz, 1H), 4.30(dd, J=11.0, 6.2 Hz, 1H), 3.72 (s, 3H), 3.4 and 2.8 (Abq, J=5.5, 3 Hz,2H),Step C

A dichloroethane (10 mL) solution containing the aldehyde from previousstep (530 mg, 2.67 mmol), 4-spiroindenylpiperidine hydrochloride (475mg, 2.14 mmol), diisopropylethylamine (390 μL, 2.20 mmol) was treatedwith sodium triacetoxyborohydride (2.27 g, 10.7 mmol) and stirred atroom temperature overnight. The reaction was quenched by pouring ontosaturated aqueous solution of sodium bicarbonate (20 mL), and extractedwith dichloromethane (4×50 mL). The combined extracts were washed withbrine (1×30 mL), and the solvent was evaporated under reduced pressureto leave 711 mg (90%) of the desired product. It was used in thesubsequent step without any additional purification.Step D

The amine-ester intermediate, synthesis of which was described inprevious step (710 mg, 1.89 mmol) was dissolved in dioxane (6 mL),treated with HCl (2N, 2.0 mL) and heated to 80° C. until all startingmaterial has disappeared, about 3 hrs. The reaction mixture wasevaporated to dryness, the residual crude product was triturated withacetone/ether mixture to leave 705 mg (96%) in a form of an off whitesolid.

EXAMPLE 34

The solution of the acid Intermediate 25 (15.4 mg, 0.0395 mmol) and3-trifluoromethoxybenzylamine (8.2 mg, 0.043 mmol) in dichloromethane (2mL) was treated with 1-hydroxy-7-azabenzotriazole (5.4 mg, 0.040 mmol),diisopropylethylamine (7 μL, 0.04 mmol) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 15mg, 0.08 mmol) and stirred at room temperature for 2 hr. The reactionmixture was poured onto water (5 mL), extracted with dichloromethane(3×2.5 mL). The combined organic extracts were washed with brine (1×2.5mL), dried with anhydrous magnesium sulfate and the solvent wasevaporated to dryness under reduced pressure. Preparative TLC usingethyl acetate gave 12 mg, 54%, two of pure product. MS: forC₂₉H₂₉F₃N₂O₂S [M+H]⁺ calculated: 526.19, found 527.40.

EXAMPLE 35

Example 35 was prepared in a similar manner to Example 34, substituting3-trifluoromethylbenzylamine for 3-trifluoromethoxybenzylamine. MS: forC₂₉H₂₉F₃N₂OS [M+H]⁺ calculated: 511.20, found 511.4.

EXAMPLE 36

Example 36 was prepared in a similar manner to Example 34, substituting3-iodobenzylamine for 3-trifluoromethoxybenzylamine. MS: for C₂₈H₂₉IN₂S[M+H]⁺ calculated: 569.10, found 569.3.

EXAMPLE 37

Example 37 was prepared in a similar manner to Example 34, substituting3-phenylbenzylamine for 3-trifluoromethoxybenzylamine. MS: forC₃₄H₃₄N₂OS [M+H]⁺ calculated: 519.24, found 519.50.

EXAMPLE 38

Example 38 was prepared in a similar manner to Example 34, substituting1-aminomethylnaphthalene for 3-trifluoromethoxybenzylamine. MS: forC₃₂H₃₂N₂OS [M+H]⁺ calculated: 493.22, found 493.50.

EXAMPLE 39

Example 39 was prepared in a similar manner to Example 34, substituting3,5-dichlorobenzylamine for 3-trifluoromethoxybenzylamine. MS: forC₂₈H₂₈Cl₂N₂OS [M+H]⁺ calculated: 511.13, found 511.3.

EXAMPLE 40

Example 40 was prepared in a similar manner to Example 34, substituting3-nitrobenzylamine for 3-trifluoromethoxybenzylamine. MS: forC₂₉H₂₉N₃O₃S [M+H]⁺ calculated: 488.19, found 488.3.

EXAMPLE 41

Example 41 was prepared in a similar manner to Example 34, substituting3,5-bistrifluoromethyl-α-methylbenzylamine for3-trifluoromethoxybenzylamine. MS: for C₃₁H₃₀N₂OSF₆ [M+H]⁺ calculated:593.20, found 593.4.

EXAMPLE 42

Example 42 was prepared in a similar manner to Example 34, substituting3,5-dimethoxybenzylamine for 3-trifluoromethoxybenzylamine. MS: forC₃₀H₃₄N₂O₃S [M+H]⁺ calculated: 503.23, found 503.5.

EXAMPLE 43

Example 43 was prepared in a similar manner to Example 34, substituting3,5-bistrifluoromethylbenzylalcohol for 3-trifluoromethoxybenzylamine.MS: for C₃₀H₂₇NO₂SF₆ [M+H]⁺ calculated: 580.17, found 580.4.

EXAMPLE 44

Example 44 was prepared in a similar manner to Example 34, substituting3-aminomethylpyridine for 3-trifluoromethoxybenzylamine. MS: forC₂₇H₂₉N₃OS [M+]⁺ calculated: 444.20, found 444.40.

EXAMPLE 45

Example 45 was prepared in a similar manner to Example 34, substituting2-aminomethylpyridine for 3-trifluoromethoxybenzylamine. MS: forC₂₇H₂₉N₃OS [M+H]⁺ calculated: 444.20, found 444.40.

Intermediate 26

Step A

Starting form 2-thienylacetic acid (1.437 g, 10.1 mmol) and3,3-dimethoxyethylbromide (2.63 mL, 22.2 mmol), the desired acid wassynthesized under analogous conditions as described for Intermediate 22,Step A. The crude acid (2.0212 g, 87%) could be further purified byrecrystallization from a mixture of diethyl ether and hexane (1:1).Step B

The desired amide was synthesized starting from 230 mg (1.00 mmol) ofintermediate acid from Step A and 280 mg (1.00 mmol) of3,5-bistrifluoromethylbenzylamine hydrochloride in a procedure analogousto that described for preparation of the corresponding isomeric amideunder Intermediate 22, Step B in 74% yield. ¹H NMR (CDCl₃, 500 MHz):7.76 (s, 1H), 7.71 (s, 2H), 7.29 (dd, J=5.3, 1.1 Hz, 1H), 7.00 (m, 2H),6.41 (t, J=6.0 Hz, 1H), 4.53 (d, J=6.0 Hz, 1H), 4.30 (t, J=5.0 Hz, 1H),3.29 (s, 3H), 3.28 (s, 3H), 2.47 (m, 1H).Step C

The acetal (160 mg, 0.3513 mmol), synthesis of which was described inprevious step, was dissolved in trifluoroacetic acid (2 mL), and brieflystirred (<5 minutes) at room temperature. The reaction mixture wasdiluted with diethyl ether, washed with water, saturated solution ofsodium bicarbonate, water, and brine. After drying with anhydrousmagnesium sulfate, the solvent was evaporated to dryness, and theunstable aldehyde (112 mg) was used in the subsequent step immediately.

EXAMPLE 46

Starting from Intermediate 26 (110 mg, 0.268 mmol) and4-spiroindenylpiperidine hydrochloride (78 mg, 0.351 mmol) the targetcompound was synthesized in a procedure similar to that described forthe respective isomeric Example 30 in 13% yield. ¹H NMR (CDCl₃, 500MHz): 7.95 (s, 2H), 7.80 (s, 1H), 7.30 (m, 5H), 7.0 (m, 2H), 6.78 (m,2H), 5.15 (d, J=7.32 Hz, 1H), 4.86 and 4.68 (ABq, J=14.9 Hz, 2H), 3.0(dd, J=14.9 Hz, 7.6 Hz, 1H), 2.7-2.2 (m, 10H), 1.25 (m, 2H).

EXAMPLE 47

Example 47 was prepared in a similar manner to Example 46, substituting4-phenylpiperidine hydrochloride for and 4-spiroindenylpiperidinehydrochloride. ¹H NMR (CDCl₃): 7.95 (s, 2H), 7.80 (s, 1H), 7.32 (m, 2H),7.23 (m, 3H), 6.98 (m, 2H), 5.12 (d, J=7.3 Hz, 1H), 4.84 and 4.64 (ABq,J=14.9 Hz, 2H), 3.36 (bd, J=10.5 Hz, 1H), 2.96 (dd, J=14.9, 7.8 Hz,111), 2.66-2.32 (bm, 7H), 2.05-1.68 (bm, 7H).

Intermediate 27

Step A

A solution of methyl 4-chloroacetoacetate (93 g, 0.62 mol) andthioformamide (25 g, 0.41 mol, prepared according to the publishedprocedure of Erlenmeyer, Munzi, Hel.Chim.Acta, 31, 2071, (1948)) inethyl alcohol (100 mL). Upon submerging the reaction vessel into a 90°C. preheated oil bath an exothermic reaction sets in at about 60° C.After the reaction subsided, a gentle reflux was maintained for another20 minutes. The formed solid was filtered off, and the filtrate wasevaporated to dryness. The residue was dissolved in 2N HCl (200 mL) andwashed with diethyl ether (200 mL). The pH of the aqueous solution wasset to basic (saturated solution of sodium bicarbonate), and the crudeproduct was extracted into diethyl ether (4×100 mL). The combinedorganic extracts were dried (anhydrous sodium sulfate), and the solventwas removed in vacuo. The oily residue was purified by distillation,(b.p.: 84-88° C./0.5 mmHg) to yield 22.8 g (24%) of pure product. MS:for C₆H₇NO₂S [M+H]⁺ calculated: 158.02, found 158.4.Step B

A suspension of sodium hydride (438 mg, 10.9 mmol, 60%) in DMF (10 mL)was cooled to 0° C. and with stirring, a solution of the methyl esterfrom previous step (1.563 g, 9.941 mmol) in DMF (10 mL) was added viasyringe. The anion was allowed to form for 30 minutes at 0° C.,whereupon the neat 2,2-dimethoxyethyl bromide was added, via syringe.The cooling bath was removed, and the reaction mixture was stirred atroom temperature 24 hrs. It was the diluted with diethyl ether andwashed with water. The organic phase was dried, and the solvent wasremoved in vacuo. The remaining oil was further purified by flashchromatography chromatography (Lobar, Lichroprep Si60, 40-63 μm) usingethyl acetate/hexane (6:4) eluent to give 670 mg (28%) of the desiredproduct. ¹H NMR (CDCl₃): 8.78 (d, J=2.0 Hz, 1H), 7.21 (d, J=1.8 Hz, 1H),4.33 (dd, J=6.4, 5.3 Hz, 1H), 4.12 (dd, J8.0, 6.6 Hz, 1H), 3.71 (s, 3H),3.33 (s, 3H), 3.05 (s, 3H), 2.50 (ddd, J=14.2, 8.2, 6.4 Hz, 2H), 2.24(ddd, 14.0,7.0, 5.0 Hz, 2H).Step C

The acetal from the previous step (670 mg, 2.73 mmol) was dissolved in90% trifluoroacetic acid (6.0 mL) and stirred briefly (<5 minutes) atroom temperature. The reaction mixture was diluted with diethyl etherand washed with saturated solution of sodium bicarbonate. After drying(anhydrous magnesium sulfate) and evaporation of the solvent in vacuo423 mg (78%) of the pure aldehyde was obtained. ¹H NMR (CDCl₃): 9.80 (s,1H), 8.78 (s, 1H), 7.22 (s, 1H), 4.48 (dd, J=8.5, 5.5 Hz, 1H), 3.73 (s,3H), 3.43 (dd, J=18.5, 8.5 Hz, 1H), 3.03 (dd, J=18.5, 5.5, 1H).

Intermediate 28

Step A

The solution of Intermediate 27 (210 mg, 1.05 mmol) and4-spiroindenylpiperidine hydrochloride (222 mg, 1.00 mmol) indichloroethane (15 mL) was treated with diisopropylethylamine (130 mg, 1mmol) followed by sodium triacetoxyborohydride (1.06 g, 5.0 mmol) andstirred at ambient temperature for 2 hours. The reaction was quenchedwith saturated solution of sodium bicarbonate, back-washed withdichloromethane. The combined organic extracts were dried (anhydroussodium sulfate) and evaporated to dryness. MS: for C₂₁H₂₄N₂O₂S [M+H]⁺calculated: 369.16, found 369.0.Step B

A solution of the ester from previous step (299 mg, 0.811 mmol) wasdissolved in dioxane (4 mL) and aq. Solution of lithium hydroxide wasadded (1N, 2 mL). Stirring at room temperature was continued for 1 hr,the pH was adjusted to acidic (2N HCl) and the reaction mixture wasevaporated to dryness. It was used in the next reaction step without anyfurther purification. MS: for C₂₀H₂₂N₂O₂S [M+H]⁺ calculated: 355.14,found 355.2.

EXAMPLE 48

Example 48 was prepared in a similar manner to Example 34, substitutingIntermediate 25 with Intermediate 28 and 3-trifluoromethoxybenzylaminewith 3,5-bistrifluoromethylbenzylamine. ¹H NMR (CDCl₃): 8.84 (d, J=1.8Hz, 1H), 7.87 (t, 5.5 Hz, 1H), 7.76 (s, 1H), 7.70 (s, 2H), 7.30 (m, 5H),6.82 (d, J=5.7 Hz, 1H), 6.76 (d, J=5.7 Hz, 1H), 4.60 (m, 3H), 4.10 (m,1H), 3.50 (s, 1H), 3.0 (t, 2.12 Hz, 2H), 2.55 to 2.10 (bm, 8H), 1.35(bs, 2H).

Intermediate 29

Intermediate 29 was prepared starting from 4-fluoropiperidine andIntermediate 27 as described for preparation of Intermediate 28. MS: forC₁₈H₂₂N₂O₂S [M+H]⁺ calculated: 331.14, found 331.2.

EXAMPLE 49

Example 49 was prepared in a similar manner to Example 34, substitutingIntermediate 25 with Intermediate 29 and 3-trifluoromethoxybenzylaminewith 3,5-bistrifluoromethylbenzylamine. ¹H NMR (CDCl₃): 8.84 (8.82 (d,J=2.1 Hz, 1H), 7.94 (t, J=5.7 Hz, 1H), 7.76 (s, 1H), 7.70 (s, 2H), 7.32to 7.18 (m, 6H), 4.60 (m, 2H), 3.05 (d, J=11.2 Hz, 1H), 3.00 (d, J=11.2Hz, 1H), 2.55 to 2.35 (bm, 4H), 2.25 to 2.05 (bm, 4H), 1.88 to 1.70 (bm,4H).

Intermediate 30

Step A

To a suspension of sodium hydride (1.446 g, 36.15 mmol, 60%) in DMF (30mL) was added at 0° C. ethyl 3-pyridylacetate and stirred at thistemperature for 1 hrs, and another 30 minutes at room temperature. Thesolution was re-cooled to 0° C. and neat 2,2-dimethoxyl-bromoethane(5.05 mL, 47 mmol) was added via syringe. The cooling bath was removedand the reaction mixture was stirred at room temperature overnight. Itwas diluted with diethyl ether (200 mL) and washed with water (2×50 mL).The organic phase was dried (anhydrous magnesium sulfate), and thesolvent was removed on Rotavap. The remaining oil was purified by vacuumdistillation (b.p.: 138-140° C./0.1 mmHg) to yield 6.58 g (79%) of thedesired product. ¹H NMR (CDCl₃): 8.55 (bd, J=3.2 Hz, 1H), 7.68, (bd,J=8.0 Hz, 1H), 7.27 (m, 1H), 4.25 (bt, 5.5 Hz, 1H), 4,12 (m, 2H), 3.74(t, J=7.3 Hz, 1H), 3.32 (s, 3H), 3.28 (s, 3H), 2.4 (m, 1H), 1.99 (ddd,J=14.0, 6.9, 5.3 Hz, 1H), 1.21 (t, J=7.1 Hz, 3H).Step B

The acetal intermediate from previous step (518 mg, 2.045 mmol) wasdissolved in TFA (5 mL) and stirred at room temperature briefly. Thereaction mixture was diluted with diethyl ether and washed withsaturated solution of sodium bicarbonate. The aqueous phases werecombined and back washed with chloroform (3×50 mL). The combined organicextracts were dried with anhydrous magnesium sulfate and the solvent wasremoved in vacuo. The remaining oil was pure enough to perform thesubsequent step without any additional purification. ¹H NMR (CDCl₃):9.74 (s, 1H), 8.51 (m, 2H), 7.59 (dt, J=8.0, 2.0 Hz, 1H), 7.24 (dd,J=8.0, 4.8 Hz, 1H), 4.11 (m, 3H), 3.38 (dd, J=18.8, 9.6 Hz, 1H), 2.80(dd, J=18.5, 5.0 Hz, 1H), 1.16 (t, 3=7.32 Hz, 3H).

Intermediate 31

Step A

Intermediate 31 was prepared starting from Intermediate 30 and4-phenylpiperidine using an analogous procedure as described for thepreparation of Intermediate 28, Step A. MS: for C₂₂H₂₈N₂O₂ [M+E]⁺calculated: 353.22, found 353.0.Step B

A solution of the ester from previous step (204 mg, 0.5992 mmol) wasdissolved in 10 mL of dioxane and aqueous solution of lithium hydroxide(1.0 M, 2.0 mL) was added. The reaction mixture was stirred at roomtemperature until HPLC indicated complete hydrolysis (about 90 minutes).The pH was set acidic (2N HCl) and the entire reaction mixture wasevaporated to dryness. It was used in the amide forming step withoutadditional purification. MS: for C₂₀H₂₄N₂O₂ [M+H]⁺ calculated: 325.18,found 325.2.

EXAMPLE 50

Example 50 was synthesized starting from acid Intermediate 31 and3,5-bistrifluoromethylbenzylamine according to a procedure described forpreparation of Example 34. MS: for C₂₉H₂₉N₃OF₆ [M+H]⁺ calculated:550.22, found 550.4.

Intermediate 32

Intermediate 32 was prepared according to Step A and B described forIntermediate 31, except that 4-phenylpiperidine was replaced with4-spiroindenylpiperidine in Step A. Both ester and the acid gavesatisfactory MS results.

EXAMPLE 51

Example 51 was synthesized starting from acid Intermediate 32 and3,5-bistrifluoromethylbenzylamine according to a procedure described forpreparation of Example 34. MS: for C₃₁H₂₉N₃OF₆ [M+E]⁺ calculated:574.22, found 574.3.

Intermediate 33

Ethyl(2-tert-butoxycarbonylimino-3-tert-butoxycarbonylthiazol-4-yl)acetate

A mixture of 186 g (1.00 mol) ethyl (2-aminothiazol-4-yl)acetate and 436g (2.00 mol) di-tert-butyl dicarbonate in 500 mL of DMSO was stirred atRT until the entire mixture solidified (˜5 days). The reaction mixtureis transferred into a stirred mixture (1L) of ice-water in a 2 literbeak. The precipitate was filtered, washed with water (3 times),dissolved in 1500 mL of CH₂Cl₂. The organic layer was washed with water(3 times), dried over Na2SO4 and filtered. The filtrates were condensedto ˜500 mL of volume. To the above mixture was added 1000 mL of hexane.The resulting crystals were collected by filtration and washing withhexane and drying in vacuo. The title compound was obtained aslight-yellow solid (278 g, 72% yield). ¹H NMR (300 MHz, CDCl₃): δ 1.23(t, 3H), 1.50 (s, 9H), 1.58 (s, 9H), 3.70 (s, 2H), 4.13 (q, 2H), 6.23(s, 1H). Mass Spectrum (NH₃—CI): m/z 387 (M+1).

Intermediate 34

Ethyl 2-(2-tert-butoxycarbonylaminothiazol-yl)-4-pentenoate

A solution of 232 g (600 mmol) ofEthyl(2-tert-butoxycarbonylimino-3-tert-butoxycarbonylthiazol-4-yl)(Intermediate 33) in 1500 mL of THF at −78° C. was treated with 252 mL(630 mmol) of 2.5 M n-butyl lithium in hexane for 30 min. To theresulting red solution was added a neat solution of 57 mL (660 mmol) ofallyl bromide. The reaction was stirred at −78° C. for 2 h and thenwarmed to 0° C. and stirred for 0.5 h. The reaction was quenched with100 g of citric acid in 1000 mL of water. The mixture was stirredovernight, evaporated to remove THF and extracted with CH₂Cl₂ (2×1000mL). The combined organic phases were washed with brine and dried overNa2SO4 and concentrtaed in vacuo. Flash chromatography on silica gel(2×500 g) using 1:9 v/v EtOAc/hexanes as the eluant afforded 184 g (94%)of the title compound as an oil. ¹H NMR (300 MHz, CDCl₃): δ 1.19 (m,3H), 1.50 (s, 9H), 2.60 (m, 1H), 2.68 (m, 1H), 3.90 (t, 1H), 4.12 (m,2H), 5.08 (m, 2H), 5.28 (m, 1H), 6.68 (s, 1H). Mass Spectrum (NH₃—CI):m/z 327 (M+1).

Intermediate 35

Ethyl 2-(2-tert-butoxycarbonylaminothiazol-yl)-2-methyl-4-pentenoate

A solution of 5.0 g (15 mmol) of Ethyl2-(2-tert-butoxycarbonylaminothiazol-yl)-4-pentenoate (Intermediate 34)in 100 mL of THF at −78° C. was treated with 25 mL (43 mmol) of 1.7 Mt-butyl lithium in hexane for 30 min. To the resulting red solution wasadded a neat solution of 2.82 g (20 mmol) of iodomethane. The reactionwas stirred at −78° C. for 2 h and then warmed to 0° C. and stirred for0.5 h. The reaction was quenched with 10 g of citric acid in 100 mL ofwater. The mixture was stirred overnight, evaporated to remove THF andextracted with CH2Cl2 (2×100 mL). The combined organic phases werewashed with brine and dried over Na2SO4 and concentrtaed in vacuo. MPLCusing 1:9 v/v EtOAc/hexanes as the eluant afforded 0.8 g of the titlecompound as an oil. ¹H NMR (300 MHz, CDCl₃): δ 1.15-1.22 (m, 3H),1.42-1.67 (d, 12H), 2.67-2.76 (m, 2H), 4.094.17 (m, 2H), 5.00-5.10 (m,2H), 5.50-5.65 (m, 1H), 6.63 (1, 1H), 7.91 (wide, 1H).

Intermediate 36

Ethyl 2-(2-tert-butoxycarbonylaminothiazol-4-yl)-3-formylpropanoate

A mixture of 150 g (460 mmol) of ethyl2-(2-tert-butoxycarbonylaminothiazol-yl)₄-pentenoate (Intermediate 34),57 g (470 mmol) of N-methyl morpholine oxide and 1.0 g of osmiumtetroxide in 1250 mL of 4/1 v/v acetone/water was stirred at RT for 1.5h. To the mixture was added 100 g of solid sodium bisulfate andcontinued to stir for 0.5 h. The solid was removed by filtration andwashing with acetone. The filtrates were combined and evaporated. Theresidue was diluted with 1000 mL of water and 2000 mL of ethyl acetate.The organic phase was separated and washed with brine (3×1000 mL), driedover Na2SO4 and condensed in vacuo. The residue was redissolved in 1500mL of methanol and 1000 mL of water. 148 g of sodium periodate wasadded. The mixture was stirred for one hour, The solid was discarded byfiltration and washing with methanol. The filtrates were condensed invacuo and the reside was dissolved in 1000 mL of ethyl acetate. Theorganic layer was washed with brine (2×1000 mL), dried over Na2SO4 andevaporated until the solid formed. 1000 mL of hexane was added and theflask was allowed to stand at RT to let crystallization proceed. Thesolid was collected by filtration and washing with hexane and drying invacuo. 79 g of the title compound was obtained as white solid. Themother liquid was condensed and the residue was suspended in hexane. Asecond crop of solid (24 g) was obtained as a yellow-solid. The motherliquid was condensed again to afford a brown solid (22 g) whichcontained impurity.

¹H NMR (300 MHz, CDCl₃): δ 1.21 (t, 3H), 1.53 (s, 9H), 2.95 (q, 2H),3.12 (m, 1H), 4.16 (m, 3H), 4.26 (m, 1H), 6.66 (s, 1H), 8.78 (broad,1H), 9.72 (s, 1H). Mass Spectrum (NH₃—CI): m/z 329 (M+1).

Intermediate 37

Ethyl2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-methyl-4-formylpropanoate

A mixture of 0.60 g (2.0 mmol) of Ethyl2-(2-tert-butoxycarbonylaminothiazol-yl)-2-methyl-4-pentenoate(Intermediate 35), 0.22 g (2.0 mmol) of N-methyl morpholine oxide and 20mg of osmium tetroxide in 25 mL of 4/1 v/v acetone/water was stirred atRT for 1.5 h. To the mixture was added 1.0 g of solid sodium bisulfateand continued to stir for 0.5 h. The solid was removed by filtration andwashing with acetone. The filtrates were combined and evaporated. Theresidue was diluted with 20 mL of water and 40 mL of ethyl acetate. Theorganic phase was separated and washed with brine (3×20 mL), dried overNa2SO4 and condensed in vacuo. The residue was redissolved in 20 mL ofmethanol and 20 mL of water. 0.64 g of sodium periodate was added. Themixture was stirred for one hour, The solid was discarded by filtrationand washing with methanol. The filtrates were condensed in vacuo and theresidue was dissolved in 100 mL of ethyl acetate. The organic layer waswashed with brine (2×100 mL), dried over Na2SO4 and evaporated to affordthe title compound as a light yellow oil. ¹H NMR (300 MD, CDCl₃): δδ1.15-1.22 (m, 3H), 1.42-1.46 (s, 9H), 1.60 (s, 3H), 2.45-2.52 (m, 2H),4.10-4.20 (m, 2H), 6.50 (s, 1H), 9.65 (s, 1H).

Intermediate 38

Ethyl2-(2-tert-butoxycarbonylamino-thiazol-4-yl)-4-(phenyl-4′-piperidine)butanoate

A mixture of 3.42 g (10 mmol) of ethyl2-(2-tert-butoxycarbonylaminothiazolyl)-3-formylpropanoate (Intermediate36), 1.61 g (10 mmol) of phenylpiperidine hydrochloride, 2.6 g (20 mmol)of DIEA and 4.22 g (20 mmol) of sodium triacetoxyborohydride in 20 mL ofCH2Cl2 at RT was stirred for 0.5 h. The reaction mixture was dilutedwith 50 mL of CH2Cl2 and washed with water (3×100 mL). The organic phasewas dried over Na2SO4 and concentrated in vacuo. 4.55 g (96%) of thetitle compound was obtained as a gummy material. ¹H NMR (300 MHz,CDCl₃): δ 1.21 (t, 3H), 1.53 (s, 9H), 1.70-1.90 (m, 4H), 1.95-2.15 (m,3H), 2.20-2.55 (m, 4H), 3.00-3.10 (m, 2H), 3.77 (t, 1H), 4.104.20 (m,2H), 6.69 (s, 1H), 7.18-7.35 (m, 5H). Mass Spectrum (NH₃—CI): m/z 474(M+1).

Intermediate 39

2-(2-tert-butoxycarbonylamino-thiazol-4-yl)-)(phenyl-4′-piperidine)butanoicacid

A mixture of 3.0 g (6.3 mmol) of ethyl2-(2-tert-butoxycarbonylamino-thiazol-4-yl)-4-(phenyl-4′-piperidine)butanoate(Intermediate 38) and 0.53 g (12.6 mmol) of lithium hydroxidemonohydrate in a solution of 60 mL of THF and 20 mL of water was heatedat 60° C. for 2 h. The entire mixture was poured onto a silica gelcolumn (50 g) and eluted out with 1/4 v/v MeOH/CH2Cl2. Evaporation invacuo afforded a light yellow solid. The solid was further dissolved in50 mL of toluene and evaporated in vacuo. 2.5 g of the title product wasobtained as a fluffy solid. Mass Spectrum (NH₃—CI): m/z 446 (M+1).

Table 10 shows a number of Intermediates that were prepared in the samefashion as described for Intermediates 38 and 39. TABLE 10 Intermediates38a-k and 39a-k

Inter- 38 (M + 1) 39 (M + 1) mediate Amine R1 R = Et R = H A

H 492 464 B

H 498 470 C

Me 512 484 D

H 512 484 E

H 512 484 F

H 512 484 G

H 398 370 H

H 400 372 I

H 493 465 J

H 489 462 k

H 489 462

Intermediate 40

Step A: Bis-(trifluoromethyl)phenylethanol

To a solution of bis(trifluoromethyl)benzaldehyde (20 g, 0.0826 mol) in200 mL of THF at −78° C. was added dropwise a solution of 84 mL ofmethylmagnesium bromide (1M, 0.084 mol) in butyl ether. The temperaturewas raised up to RT. The entire mixture was poured into a stirredmixture of ammonium chloride, ice and water (1000 mL), extracted withethyl acetate (2×1000 mL). The organic phases were dried over NaSO4.Evaporation in vacuo afforded the title compound as a light yellowliquid (20.64 g, 98%).

Step B: N-(Bis[trifluoromethyl]phenylethyl)phthalimide

To a stirred solution of bis-(trifluoromethyl)phenylethanol (20.64 g,0.08 mol), phthalimide (11.76 g, 0.08 mol) and triphenylphosphine (22.6g, 0.1 mol) in 150 mL of THF at 0 C was added dropwise a solution ofDEAD (17.4 g, 0.1 mol) in 100 mL of THF in 30 min. The mixture was thenstirred at RT overnight, condensed in vacuo. Flash chromatography onsilica gel (500 g) afforded the title compound as a light yellow solid.

Step C: Bis-(trifluoromethyl)phenylethylamine

A mixture of N-(bis-[trifluoromethyl]phenylethyl)phthalimide (allmaterial, ˜0.076 mol) and hydrazine (3.2 g, 0.1 mol) in 500 mL ofethanol was stirred at 80 C for 2 h. The flask was put into refrigeratorovernight. The solid was removed by filtration and washing with ethanol.The filtrates were combined and evaporated in vacuo.

Step D: N-Butoxycarbonyl-bis-(trifluoromethyl)phenylethylamine

The above residue (Step C) was stirred with di-tert-butyl dicarbonate(17 g, 0.08 mol) in 200 mL of dioxane for 30 min, evaporated in vacuo.The residue was purified by flash chromatography on silica gel (400 g)using 30% EtOAc/hexanes. The title compound (20.7 g) was obtained as awhite solid.

Step E: Bis-(trifluoromethyl)phenylethylamine hydrochloride

N-Butoxycarbonyl-bis-(trifluoromethyl)phenylethylamine (20.7 g) wasstirred with a solution of 100 mL of 4M HCl dioxane for 2 h. The mixturewas evaporated and dried in vacuo afford the title compound as a whitesolid (15.6 g).

Intermediate 41

2-(2-tert-butoxycarbonylamino-thiazolyl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide

A mixture of 2.5 g (5.6 mmol) of2-(2-tert-butoxycarbonylamino-thiazol-4-yl)-4′-(phenyl-4′-piperidine)butanoicacid (intermediate 39) and 1.95 g (7 mmol) ofbis-(trifluoromethyl)benzylamine hydrochloride in 50 mL of CH2Cl2 wasstirred for 2 h. The reaction mixture was diluted with 100 mL of CH2Cl2and washed with water (3×100 mL), dried over Na2SO4 and evaporated invacuo. Flash chromatography on 50 g of silica gel using 1:9 v/vmethanol/methylene chloride afforded 2.8 g (75%) of the title compoundas a light-yellow solid. ¹H NMR (300 MHz, CDCl₃): δ 1.52 (s, 9H),1.60-1.80 (m, 4H), 1.90-2.10 (m, 3H), 2.22-2.50 (m, 4H), 2.90-3.10 (m,2H), 3.75 (b, 1H), 4.50 (m, 2H), 6.70 (s, 1H), 7.14-7.30 (m, 5H), 7.60(broad, 1H), 7.63 (s, 2H), 7.73 (s, 1H), 8.50 (broad, 1H). Mass Spectrum(NH₃—CI): m/z 671 (M+1).

Intermediate 42

2-(2-Amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide

2.5 g (5.6 mmol) of2-(2-tert-butoxycarbonylamino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide(Intermediate 41) was stirred with 50 mL of 95:5 v/v TFA/H2O for 2 h.TFA was removed by vacuo and the residue was purified on preparative TLCusing 1:9 [(1:9 aq. NH₄OH/MeOH)/CH2Cl2). 1.70 g (81%) of the titlecompound was obtained as a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ1.62-1.95 (m, 3H), 2.00-2.20 (m, 3H), 2.20-2.60 (m, 4H), 2.75-3.10 (m,3H), 3.70 (t, 1H), 4.55 (m, 2H), 5.35 (s, 2H), 6.32 (s, 1H), 7.18-7.31(m, 5H), 7.68-7.74 (m, 4H). Mass Spectrum (NH₃—CI): m/z 571 (M+1).

Table 11 shows other Intermediates prepared in the same fashion asIntermediates 41 and 42. TABLE 11 Intermediates 41a-n and 42a-n

41 42 (M + 1) (M + 1) Inter- R = R = mediate Amine R1 R2 NHBoc NH2 A

H H 689 589 B

H H 695 595 C

Me H 709 609 D

H Me 709 609 E

H H 697 597 F

H H 709 609 G

H H 711 611 H

H H 709 609 I

H H 709 609 J

H H 595 495 K

H H 597 497 L

H H 690 590 M

H H 686 586 N

H H 686 586

EXAMPLE 52

2-(2-Acetylamino-thiazol-4-yl)-N-(3.5-bis-trifluoromethyl-benzyl)-(phenyl-4′-piperidine)-1′-butyramide

A mixture of 0.571 g (1 mmol) of2-(2-Amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide(intermediate 42), 0.5 mL of acetic anhydride and 1.0 mL of pyridine in5 mL of CH2Cl2 was stirred at RT overnight. Excess reagents were removedin vacuo. The residue was purified on preparative TLC using 1:9 [(1:9aq. NH4OH/MeOH)/CH2Cl2). 0.53 g (87%) of the title compound was obtainedas a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ 1.62-1.95 (m, 3H),2.00-2.20 (m, 3H), 2.20-2.60 (m, 4H), 2.75-3.10 (m, 3H), 3.70 (t, 1H),4.55 (m, 2H), 5.35 (s, 2H), 6.32 (s, 1H), 7.18-7.31 (m, 5H), 7.68-7.74(m, 4H). Mass Spectrum (NH₃—CI): m/z 613 (M+1).

As shown in Table 12, a number of compounds were prepared in the samefashion as 52 starting from Intermediates 42a-n and the correspondingpiperidines, piperazines and morphilines. TABLE 12 EXAMPLES 52a-n

m/z Example Amine R1 R2 (M + 1) 52a

H H 631 52b

H H 637 52c

H Me 651 52d

Me H 651 52e

H H 639 52f

H H 651 52g

H H 653 52h

H H 651 52i

H H 651 52j

H H 537 52k

H H 539 52l

H H 632 52m

H H 628 52n

H H 628

EXAMPLE 52h-(S)

EXAMPLE 52h-(R)

The two diastereomers of 52h which are epimeric α-to the amide carbonyl,could be separated into two pure single isomers using chiral HPLC(ChiralPak OD column, Hexane/Ethanol). Example 52h-(S): fast isomer,more active; Example 52h-(R): slow isomer, less active.

EXAMPLE 53

2-(2-cyclopropanecarbonylamino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′piperidine)-1′-butyramide

A mixture of 0.571 g (0.1 mmol) of2-(2-Amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide(Intermediate 42), 0.27 g of cyclopropanecarboxylic acid, 0.57 g of EDAChydrochloride, a granule of DMAP (cat.) in 5 mL of CH2C12 was stirred atRT overnight. Excess reagents were removed in vacuo. The residue waspurified on preparative TLC using 1:9 [(1:9 aq. NH4OH/MeOH)/CH2Cl2).0.51 g (80%) of the title compound was obtained as a yellow solid. MassSpectrum (NH3—CI): m/z 639 (M+1).

The examples 54-70 were prepared starting from the correspondingaminothiazole intermediates according to the same procedure as shown forthe preparation of Example 53. TABLE 13 EXAMPLES 54-70

m/z Example Amine R (M + 1) Note 54

655 55

641 56

627 57

685 58

671 From Hydrolysis of Example 57 59

675/677 60

728 61

628 From TFA Treatment of Example 60 62

675 63

785 64

771 65

693 (hold) 66

755 67

741 68

727 69

713 70

719

EXAMPLE 71

2-Acetylmethylamino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′piperidine)-1′-butyramide

A mixture of 0.061 g (1 mmol) of2-(2-Acetylamino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide(Example 52), 0.5 mL of methanol, 0.52 g of triphenylphosphine and 0.14g of DEAD in 5 mL of THF was stirred at RT overnight. Excess reagentswere removed in vacuo. The residue was purified on preparative TLC using1:9 [(1:9 aq. NH4OH/MeOH)/CH2Cl2). 0.050 g (82%) of the title compoundwas obtained as a yellow solid. Mass Spectrum (NH₃—CI): m/z 627 (M+1).

EXAMPLE 72

2-(2-[N-Butanoicacid]amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide

A mixture of 0.0675 g (0.1 mmol) of2-(2-[4-Chlorobutanoyl]amino-thiazolyl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4″-piperidine)-1′-butyramide(Example 59), 0.03 g of sodium hydride in 2 mL of DMF was stirred at RTovernight. Excess reagents were removed in vacuo. The residue waspurified on preparative LC using 1:9 [(1:9 aq. NH4OH/MeOH)/CH2Cl2).0.048 g (71%) of the title compound was obtained as a yellow solid. MassSpectrum (NH₃—CI): m/z 639 (M+1).

EXAMPLE 73

2-(2-methylaminocarbonyl]amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide

A mixture of 0.115 g (0.2 mmol) of2-(2-Amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)₄-(phenyl-4′-piperidine)-1′-butyramide(Intermediate 42), 0.03 g of methylisocyanate in 5 mL of CH2Cl2 washeated in a capped vial at 60° C. overnight. Excess reagents wereremoved in vacuo. The residue was purified on preparative TLC using 1:9[(1:9 aq. NH4OH/MeOH)/CH2Cl2). 0.082 g (65%) of the title compound wasobtained as a white solid. Mass Spectrum (NH₃—CI): m/z 628 (M+1).

The Examples 74-79 in Table 14 were prepared according to the sameprocedure as described for Example 73 starting from the correspondingaminothiazole Intermediates described previously and methylisocyanate.TABLE 14 EXAMPLES 74-79

Example Amine (M + 1) Example Amine (M + 1) 74

646 77

666 75

637 78

552 76

654 79

554

EXAMPLE 80

2-(2-[Phenylaminocarbonyl]amino-thiazolyl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butramide

A mixture of 0.115 g (0.2 mmol) of2-(2-Amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide(Intermediate 42), 0.036 g of phenylisocyanate in 5 mL of CH2Cl2 washeated in a capped vial at 60° C. overnight. Excess reagents wereremoved in vacuo. The residue was purified on preparative TLC using 1:9[(1:9 aq. NH4OH/MeOH)/CH2Cl2). 0.10 g (72%) of the title compound wasobtained as a white solid. Mass Spectrum (NH₃—CI): m/z 690 (M+1).

EXAMPLE 81

2-(2-[Pyrrolidinylcarbonyl]amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl]-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide

A mixture of 0.115 g (0.2 mmol) of2-(2-Amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide(Intermediate 42) and 0.5 mL of phosgene (˜20% in toluene) in 5 mL ofCH2Cl2 was stirred in a capped vial for 1 h. Then 0.10 g of pyrrolidinewas added and continued to be stirred for 2 h. Excess reagents wereremoved in vacuo. The residue was purified on preparative TLC using 1:9[(1:9 aq. NH4OH/MeOH)/CH2Cl2). 0.072 g (54%) of the title compound wasobtained as a white solid. Mass Spectrum (NH₃—CI): m/z 668 (M+1).

EXAMPLE 82

2-(2-[Dimethylaminocarbonyl]amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide

A mixture of 0.115 g (1 mmol) of2-(2-Amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide(Intermediate 42) and 0.032 g of dimethylaminocarbonyl chloride in 5 mLof CH2Cl2 was stirred in a capped vialovernight. Excess reagents wereremoved in vacuo. The residue was purified on preparative TLC using 1:9[(1:9 aq. NH4OH/MeOH)/CH2Cl2). 0.073 g (57%) of the title compound wasobtained as a yellow solid. Mass Spectrum (NH₃—CI): m/z 642 (M+1).

EXAMPLE 83

Step A:2-(2-[N-Butoxyaminoethyl]butoxycarbonylamino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide

A mixture of 0.134 g (0.2 mmol) of2-(2-Butoxycarbonylamino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide(Intermediate 41), 0.5 g of butoxycarbonylaminoethanol, 0.52 g oftriphenylphosphine and 0.14 g of DEAD in 5 mL of THF was stirred at RTovernight. Excess reagents were removed in vacuo. The residue waspurified on preparative TLC using 1:9 [(1:9 aq. NH4OH/MeOH)/CH2Cl2).0.127 g (78%) of the title compound was obtained as a solid. MassSpectrum (NH₃—CI): m/z 814 (M+1).

Step B:2-(2-Aminoethylamino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide

A mixture of 0.127 g (0.15 mmol) of2-(2-[N-Butoxyaminoethyl]butoxycarbonylamino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide(from Example 83, Step A) and 1.0 mL of TFA was stirred at RT for 30min. Excess reagents were removed in vacuo. The residue was purified onpreparative TLC using 1:9 [(1:9 aq. NH4OH/MeOH)/CH2Cl2). 0.090 g (94%)of the title compound was obtained as a gummy solid. Mass Spectrum(NH₃—CI): m/z 614 (M+1).

Step C:2-(2-N-[2-Imidazolidon]-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′:piperidine)-1′-butyramide

A mixture of 0.090 g (0.146 mmol) of2-(2-Aminoethylamino-thiazol-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide(from Example 83, Step B), 0.2 g of triphosgene, 0.2 mL of DIEA in 5 mLof CH2Cl2 was stirred at RT for 3 h. Excess reagents were removed invacuo. The residue was purified on preparative TLC using 1:9 [(1:9 aq.NH4OH/MeOH)/CH2Cl2). 0.073 g (78%) of the title compound was obtained asa white solid. Mass Spectrum (NH₃—CI): m/z 640 (M+1).

EXAMPLE 84

2-(2-[Methoxycarbonyl]amino-thiazol-4-yl)-N-(3,5-bis-trifluoro th1-benzyl)-4(phenyl-4′-piperidine)-1′-butyramide

A mixture of 0.115 g (0.2 mmol) of2-(2-Amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)₄(phenyl-4′-piperidine)-1′-butyramide(Intermediate 42), 0.5 mL of methyoxycarbonyl chloride and 1.0 mL ofpyridine in 5 mL of CH2Cl2 was stirred in a capped vial for overnight.Excess reagents were removed in vacuo. The residue was purified onpreparative TLC using 1:9 [(1:9 aq. NH4OH/MeOH)/CH2Cl2). 0.117 g (93%)of the title compound was obtained as a yellow solid. Mass Spectrum(NH₃—CI): m/z 629 (M+1). The Examples 85-86 in Table 15 were synthesizedaccording to the same procedure as that of Example 84 starting from theappropriate aminothiazole Intermediate (described previously). TABLE 15EXAMPLES 85-86

Example Amine (M + 1) Example Amine (M + 1) 48

647 49

652

EXAMPLE 87

2-(2-guanidino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide

A mixture of 0.2 g (0.35 mmol) of2-(2-Amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-4-(phenyl-4′-piperidine)-1′-butyramide(Intermediate 42) and 0.13 g of 1H-pyrazole-1-carboxamidinehydrochloride in 10 mL of nitrobenzene in a capped pressure tube wasstirred at ˜210° C. for 30 min Excess reagents were removed in vacuo.The residue was purified on preparative TLC using 1:9 [(1:9 aq.NH4OH/MeOH)/CH2Cl2). 0.08 g (37%) of the title compound was obtained asa yellow solid. Mass Spectrum (NH₃—CI): m/z 613 (M+1).

The examples 88-92 in Table 16 were prepared according to similarprocedures to Example 87 from Intermediates described previously. TABLE16 EXAMPLES 88-92

Example Amine (M + 1) Example Amine (M + 1) 88

631 91

632 89

637 92

628 90

628

Intermediate 43

Step 1

DMF (10 mL) was deoxygenated by bubbling with nitrogen for 30 minutesbefore a solution of 3-amino-5-bromobenzotrifluoride (500 mg, 2.08 mmol)in DMF was added. The solution was bubbled with nitrogen for another 10minutes fore zinc cyanide (147 mg, 1.25 mmol) andTetrakis(triphenylphospine)-Pd (96 mg, 0.083 mmol) were added. Themixture was deoxygenated for another 15 minutes before heated to 80° C.in a sealed high pressure tube overnight. The reaction was diluted withethyl acetate, washed with an ammonia hydroxide solution (2×), andconcentrated in vacuo. The crude product was purified by preparationplates (30/70 ethyl acetate/hexanes) to yield 43-1 (289 mg, 74.5%). ¹HNMR (400 MHz, CDCl3) δ 7.25 (d, J=0.6 Hz, 1H), 7.08 (s, 1H), 7.06 (d,J=0.9 Hz, 1H). LC-MS: MW calculated 186.13, found 227.8(M⁺Acetonitrile⁺).Step 2

A mixture of Copper(II) bromide (415 mg, 1.86 mmol), tert-butylnitrite(277 μL, 2.33 mmol), and anhydrous acetonitrile (7 mL), was cooled to 0°C. before a solution of 43-1 (289 mg, 1.55 mmol) in anhydrousacetonitrile (2 mL) was added slowly. After completion of addition, thereaction mixture was heated to 65° C. and monitored by TLC. The mixturewas cooled to RT before poured into 20% aqueous HCl solution andextracted with ether. The organic layer was washed with 20% aqueous HClsolution, dried over anhydrous MgSO₄, and concentrated in vacuo. Thecrude product was purified by a preparation plate (25/75, ethylacetate/hexanes) to yield 43-2 (230 mg, 59.3%). LC-MS: MW calculated248.94, found 249.02.Step 3

43-2 (50 mg, 0.200 mmol) was dissolved in THF (1 mL) before 1M Borane inTHF (1 mL) was added. The mixture was stirred at RT overnight beforeconcentrated in vacuo. The residue was redissolved in a solution of 1%HCl (4N in dioxane) in methanol and heated at 50° C. overnight. Solventwas stripped off and redissolved in 1% HCl in methanol. This process wasrepeated three times to get ride of excess borane and yield crude 43-3(50 mg, 98.4%). LC-MS: MW calculated 252.97, found 253.8.

Intermediate 44

Intermediate 44 was prepared as detailed in Intermediate 43 usingCu({[)Cl₂ instead of Cu(II)Br₂ in Step 2. 1H NMR (400 MHz, CD3OD) δ 7.80(m, 3H), 4.22 (s, 2H).

Intermediate 45

Step 1

43-1 (500 mg, 2.69 mmol) was added to a mixture of concentrated HCl andwater (5mL: 5mL) (solution A). Sodium nitrite (342 mg, 4.95 mmol) wasdissolved in water (5 mL) (solution B). The two solutions were cooled to0° C. separately before solution B was added to solution A slowly. Atend of addition, KI-starch paper was used to test presence of nitrousacid. A solution of KI (765 mg, 4.61 mmol) in water (5 mL) was added andstirred for 30 minutes before heated at 100° C. until no nitrogen gasevolution occurred. The mixture was cooled to RT and extracted withether (2×), dried over anhydrous NaSO₄, and concentrated in vacuo. Crudeproduct was purified by preparation plates (40/60, ethylacetate/hexanes) to yield 45-1 (580 mg, 72.8%). 1H NMR (300 MHz, CDCl3)δ 8.18 (d, J=1.38 Hz, 2H), 7.89 (t, J=0.73 Hz, 1H).Step 2

Intermediate 45

Intermediate 45 was prepared as detailed in Intermediate 43-Step 3. 1HNMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 4.19(s, 2H).

EXAMPLE 93

A mixture of Intermediate 43 (50 mg, 0.172-mmol),2-(2-acetamido-thiazol-4-yl)-4-(phenyl-4′-piperidine)butanoic acid(prepared in an analogous fashion to Intermediate 39, 67 mg, 0.172mmol), EDC (50 mg, 0.258 mmol), and DCM (5 mL) was stirred at roomtemperature overnight before concentrated in vacuo. The concentrate waspurified by a preparation plate (5/95 MeOH/DCM) to yield Example 93 (90mg, 65.7%). LC-MS: MW calculated 622.12, found 625.2.

EXAMPLE 94

Example 94 was prepared as detailed in Example 93 using Intermediate 44instead of Intermediate 43. LC-MS: MW calculated 578.17, found 579.2.

EXAMPLE 95

Example 95 was prepared as detailed in Example 93 using Intermediate 45instead of Intermediate 43. The two enantiomers were further resolved bychiral columns. LC-MS: MW calculated 670.11, found 671.2.

EXAMPLE 96

Example 96 was prepared as detailed in Example 14-Step B using Example93 as starting material. LC-MS: MW calculated 602.22, found 603.3.

EXAMPLE 97

Example 97 was prepared as detailed in Example 15 using Example 96 asstarting material. LC-MS: MW calculated 588.20, found 589.3.

Intermediate 46

Step A:

To a solution of CuBr₂ (14.4 g, 64.4 mmol) and t-butylnitrite (9.58 mL,8.31 g, 80.5 mmol) in acetonitrile (200 mL) was aded in small portionsethyl 2-amino-4-thiazoleacetate (10.0 g, 53.7 mmol). The addition wasaccompanied by gas evolution. After 1 h no further gas evolution couldbe observed with an attached bubbler. The reaction mixture was pouredinto 2 N HCl (1 L) and washed twice with ether (500 mL ea.). Theethereal layers were combined and washed 2 N HCl (500 mL), saturatedNaHCO₃ solution (500 mL), and brine (300 mL), then dried over MgSO₄,filtered and concentrated. Purification by MPLC, eluting with 35% ethylactetate/hexane afforded 4.19 g (31%) of the desired product.

H NMR (CDCl₃, 500 MHz): δ 7.18 (t, J=1.0 Hz, 1H), 4.20 (q, =7.0 Hz, 2H),3.81 (d, J=1.0 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H).Step B:

A solution of 2-bromo-4-thiazoleacetate (3.18 g, 12.7 mmol) in DMF (25mL) at 0° C. was treated with sodium hydride (611 mg, 15.3 mmol),followed five min later with allyl bromide (1.10 mL, 1.54 g, 12.7 mmol).After 40 min at 0° C., the reaction mixture was poured into 5% citricacid solution (300 mL) and extracted twice with ether (300 mL). Thecombined ethereal layers were washed twice with water and once withbrine, dried over MgSO₄, filtered and concentrated. Purification byMPLC, eluting with 25% ethyl acetate/hexane gave 1.96 g (53%) of thedesired product as a clear oil.

H NMR (CDCl₃, 500 MHz): δ 7.12 (br s, 1H), 5.73 (m, 1H), 5.01-5.11 (m,2H), 4.12-4.22 (m, 2H), 3.93 (dd, J=7.5, 7.0 Hz, 1H1), 2.73-2.80 (m,1H), 2.64-2.71 (m, 1H), 1.24 (t, J=7.0 Hz, 3H).Step C:

The olefin prepared in Step B above (1.96 g, 6.75 mmol) was dissolved in65 mL of a 4:1 mixture by volume of acetone and water, cooled to 0° C.,then treated with NMO (949 mg, 8.10 mmol), followed by 4% aqueous OsO₄solution (2.1 mL, 0.34 mmol). After 0.5 h at 0° C. the reaction mixturewas warmed to rt and stirred for an additional 2 h, whereupon solidNaHSO₃ (4.5 g) was added. This mixture was stirred for 5 min, then theacetone was removed at rt in vacuo. The residue was diluted with etherand washed with brine. The aqueous layer was extracted four more timeswith ether and the combined ethereal layers were dried over MgSO₄,filtered and concentrated. The crude diol was dissolved in 65 mL of a1:1 mixture of MeOH/H₂O, cooled to 0° C., and treated with NaIO₄ (2.17g, 10.1 mmol). The reaction mixture was permitted to warm to rt and stirfor 45 min. The mixture was then filtered through celite, and partiallyconcentrated to remove the MeOH. The resulting mixture was diluted withbrine and extracted twice with ether. The combined ethereal layers weredried over MgSO₄, filtered, and concentrated to give 1.94 g of crudeproduct which was used as is in the subsequent step.

H NMR (CDCl₃, 500 MHz): δ 9.79 (s, 1H), 7.11 (s, 1H), 4.34 (dd, J=8.0,5.5 Hz, 1H), 4.15-4.20 (m, 2H), 3.36 (dd, J=18.5, 8.5 Hz, 1H), 3.07 (dd,J=19.0, 6.0 Hz, 1H), 1.24 (t, J=7.0 Hz, 3H).Step D:

The aldehyde intermediate from the preceding step (1.94 g, 6.65 mmol)was combined with triethylamine (1.11 mL, 807, mg, 7.98 mmol) andphenylpiperidine hydrochloride (1.58 g, 7.98 mmol) in DCM (40 mL). ThenNaB(OAc)₃H (4.23 g, 20.0 mmol) was added and the reaction mixture wasstirred at rt for 2 h. The reaction mixture was then diluted with DCM(200 mL), and washed sequentially with saturated NaHCO₃ solution, andbrine, dried over MgSO₄, filtered and concentrated to give 2.93 g ofcrude product which was used without further purification.

H NMR (CDCl₃, 500 MHz): δ 7.16-7.31 (m, 6H), 4.19 (m, 2H), 3.97 (t,J=7.0 Hz, 1H), 3.06 (app dd, J=25.5, 11.0 Hz, 2H), 2.43-2.52 (m, 3H),2.34 (m, 1H), 2.09-2.17 (m, 3H), 1.83 (br s, 4H), 1.26 (t, J=7.0 Hz,3H).Step-E:

An aqueous solution of LiOH.H₂O (334 mg, 7.96 mmol) was added to asolution of ethyl ester prepared in the preceding step (2.90 g, 6.63mmol) in 30 mL of 1:1 THF/MeOH. The reaction mixture was stirred at rtfor 4 h, then neutralized with anhydrous HCl in ether (8.0 mL, 8.0 mmol)and concentrated to dryness, affording 3.43 g of crude amino acid(contaminated with LiCl). This material was used directly in thefollowing step.Step F:

The acid prepared as described in the previous step (“6.63” mmol) wascombined with Bis-(trifluoromethyl)-benzylamine hydrochloride (2.22 g,7.96 mmol), EDC (2.54 g, 13.3 mmol), and DIEA (1.39 mL, 1.03 g, 7.96mmol) in DCM (50 mL) and stirred at rt overnight. The reaction mixturewas then diluted with DCM (200 mL) and washed with saturated NaHCO₃solution (200 mL), water (200 mL), and brine (200 mL), then dried overMgSO₄, filtered, and concentrated. Purification by flash chromatography,eluting with 0.5/4.5/95 of concentrated NH₄OH solution, MeOH and DCM,gave 2.43 g (58% for three steps) of Intermediate 46 as a yellow oil.

H NMR (CDCl₃, 500 MHz): δ 7.77 (s, 1H), 7.68 (s, 2H), 7.56 (br s, 1H),7.28 (m, 2H), 7.18 (m, 4H), 4.58 (d, J=6.0 Hz, 2H), 3.94 (t, J=7.50 Hz,1H), 2.99 (d, J=11.5 Hz, 1H), 2.89 (d, =11.0 Hz, 1H), 2.28-2.49 (m, 4H),1.98-2.15 (m, 3H), 1.81 (m, 2H), 1.61-1.71 (m, 2H). ESI-MS calc. forC27H26BrF6N3OS: 633, 635; Found: 634, 636 (M+H).

EXAMPLE 98

Thiophene-3-boronic acid (23 mg, 0.18 mmol), bromide Intermediate 46(102 mg, 0.160 mmol) and 2M aqueous Na₂CO₃ (0.4 mL, 0.8 mmol) werecombined in toluene (1 mL) and MeOH (0.4 mL). Pd(Ph₃)₂Cl₂ (6 mg, 8 μmol)was added, after which the reaction mixture was purged with Argon andstirred at 80° C. overnight. The reaction mixture was concentrated. Theresidue was dissolved in ethyl acetate and washed with water, thenbrine, dried over MgSO₄, filtered, and concentrated. Purification bypreparative TLC, eluting with 0.5/4.5/95 of concentrated NH₄OH solution,MeOH and DCM, gave 67.6 mg product which was converted to itshydrochloride salt by dissolving in DCM (1 mL), adding anhydrous 1N HClin ether (112 μL, 0.112 mmol), and concentrating to afford 71 mg (66%)of Example 98 as a white solid. ESI-MS calc. for C31H29F6N3OS2: 637;Found: 638 (M+H).

EXAMPLE 99

1-methyl-5-tributylstannyl-1H-imidazole (67 mg, 0.18 mmol), bromideIntermediate 46 (104 mg, 0.163 mmol), Ph₃As (10 mg, 0.033 mmol), LiCl(21 mg, 0.49 mmol) and Pd₂ dba₃ (7.5 mg, 8.2 μmol) were combined in NMP(2 mL) under argon and stirred at 80° C. for 48 h. Although the reactionwas incomplete, it was worked up bydiluting with ethyl acetate andwashing with saturated NaHCO₃ solution, water (3 times), and brine. Theorganic layer was dried over MgSO₄, filtered, and concentrated.Purification by preparative TLC, eluting with 0.7/6.3/93 of concentratedNH₄OH solution, MeOH and DCM, gave 12 mg of desired product. ESI-MScalc. for C31H31F6N5OS: 635; Found: 636 (M+H).

Some additional analogs prepared using the same experimental protocolsas described in Examples 98 or 99 are displayed in Table 17. TABLE 17

ESI-MS Example R calc. MW Found (M + H)⁺ 100

631 632 101

649 650 102

661 662 103

661 662 104

675 676 105

766 767 106

676 677 107

632 633 108

632 633 109

650 651 110

621 622

EXAMPLE 111

2-Aminothiazole Intermediate 42 (554 mg, 0.971 mmol) was combined withN,N′-dimethylformamide azine (276 mg, 1.94 mmol, ref. Bartlett, R. K.;Humprey, I. R. J. Chem. Soc. C 1967, 1664-1666.) and TsOH.H₂O (10 mg) intoluene (10 mL) and stirred at reflux for 12 h. Then the reactionmixture was stored at rt for 48 h. The reaction mixture was concentratedand the crude product purified by preparative TLC, eluting with0.75/6.75/92.5 of concentrated NH₄OH solution, MeOH and DCM. The productwas then converted to its hydrochloride salt by dissolving in DCM (1mL), adding anhydrous 1 N HCl in ether solution (0.65 mL, 0.65 mmol),and concentrating to give 436 mg (68%) of a white solid. ESI-MS calc.for C29H28F6N6OS: 622; Found: 623 (M+H).

EXAMPLE 112

Step A:

A suspension of sodium hydride (60% dispersion, 1.34 g, 33.4 mmol) indioxane (25 mL) was treated at rt over 0.5 h withtetraethyldimethylaminomethylene diphosponate (10.5 g, 31.8 mmol). Theaddition was exothermic and was accompanied by foaming. The mixture wasstirred at rt for 1.25 h, then 5-nitrothiophene-3-carboxylic aldehyde(5.0 g, 31.8 mmol) in dioxane (25 mL) was added. A thick oilprecipitated from the reaction mixture. The reaction temperature wasraised to 60° C. and heating was continued for 1.5 h, after which thereaction mixture was permitted to cool to rt and sit overnight. Thesolvent was removed in vacuo and the resulting residue was partitionedbetween ether and 1 N HCl solution (emulsion, insolubles). The aqueouslayer was extracted two more times with ether. The ethereal layers werecombined, washed with brine, dried over MgSO₄, filtered, andconcentrated. The resulting residue was treated with 12N HCl solution(75 mL) and stirred at reflux for 20 min. The resulting mixture wasextracted three times with ether, the ethereal layers were combined andthey, in turn, were washed with water, then brine. The organic layer wasdried over anhydrous MgSO₄, filtered and concentrated. Purification byMPLC, eluting with a 5-10% MeOH/ethyl actetate gradient provided 3.31 g(56%) of carboxylic acid.

H NMR (CD₃OD, 400 MHz): δ 7.96 (d, J=2.80 Hz, 1H), 7.62 (m, 1H), 3.68(s, 2H).Step B:

Iodomethane (1.04 mL, 2.36 g, 16.7 mmol) was added to solution of thecarboxylic acid prepared as described in the preceding step (2.97 g,15.9 mmol) and K₂CO₃ (5.49 g, 39.8 mmol) in DMF (30 mL) at 0° C. Theresulting mixture was stirred at 0° C. for 45 min, then warmed to rt andstirred for an additional 1 h. The viscous reaction mixture was dilutedwith ether and washed with water. The aqueous layer was washed a secondtime with ether and the ethereal layers were combined and rinsed threetimes with water, and once with brine. The ethereal phase was then driedover MgSO₄, filtered, and concentrated. The resulting 2.79 g of ester(87%) was used without further purification.

H NMR (CDCl₃, 300 MHz): δ 7.89 (d, J=1.8 Hz, 1H), 7.39 (m, 1H), 3.74 (s,3H), 3.65 (s, 2H).Step C:

Iron powder (3.03 g, 54.3 nmol) was added to a mixture of the esterprepared as described in the previous step (2.02 g, 10.1 mmol) andacetic anhydride (10.0 mL, 10.8 g, 106 mmol) in acetic acid (40 mL). Thetemperature was raised to 60° C. and the reaction mixture was stirredfor 1 h 10 min. The reaction mixture was filtered through celite,washing with ethyl acetate. A 3N NaOH solution was added (exotherm) andthe layers were separated. It was determined that the ester had beeninadvertantly hydrolyzed. The aqueous layer was therefore acidified withconcentrated HCl solution, and extracted ten times with ethyl acetate.The combined organic layers were dried over MgSO₄, filtered, andconcentrated to give 905 mg of acid. The acid was converted back to themethyl ester by stirring in anhydrous HCl in MeOH [prepared by addingthionyl chloride (1.33 mL, 2.16 g, 18.2 mmol) to MeOH (25 mL) at 0° C.]for 6 hrs at rt. The reaction mixture was then concentrated.Purification by MPLC (10% MeOH/DCM, then again with pure ethyl acetate,then a third time with 90% ethyl actetate/hexane) afforded 515 mg ofdesired product.

H NMR (CD₃OD, 500 MHz): δ 6.68 (m, 1H), 6.61 (d, J=1.5 Hz, 1H), 3.67 (s,3H), 3.56 (s, 2H), 2.10 (s, 3H).Step D:

To a solution of the ester prepared in Step C above (352 mg, 1.65 mmol)in THF (20 mL) at −78° C. was added dropwise 1.5 M LDA in cyclohexane(2.75 mL, 4.13 mmol). After stirring for 50 min, allyl bromide (157 □L,220 mg, 1.82 mmol) was added dropwise. Stirring was continued at −78° C.for 1.75 h, then the reaction mixture was poured into 10% aqueous citricacid solution, and extracted twice with ethyl acetate. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated. Purification by MPLC, eluting with 95% ethylactetate/hexane, provided 263 mg (63%) of the desired product.

H NMR (CDCl₃, 500 MHz): δ 7.97 (br s, 1H), 6.67 (s, 1H), 6.60 (d, J=1.5Hz, 1H), 5.71 (m, 1H), 5.00-5.10 (m, 2H), 3.66 (m, 1H), 3.67 (s, 3H),2.68-2.75 (m, 1H), 2.45-2.52 (m, 1H), 2.18 (s, 3H).Step E:

The olefin prepared in Step D above (209 mg, 0.825 mmol) was dissolvedin 10 mL of a 4:1 mixture by volume of acetone and water, then treatedwith NMO (116 mg, 0.990 mmol), followed by 4% aqueous O_(s)O₄ solution(0.26 mL, 0.041 mmol). The reaction mixture was stirred for 1.75 h, thenNaIO₄ (265 mg, 1.24 mmol) was added. This mixture was stirred for 5 min,then the acetone was removed at rt in vacuo. The residue was dilutedwith DCM and washed with brine. The aqueous layer was extracted two moretimes with DCM and six times with ether and the combined organic layerswere dried over Na₂SO₄, filtered and concentrated at rt. The crude diolwas dissolved in 10 mL of a 1:1 mixture of MeOH/H₂O, and treated withNaIO₄ (2.17 g, 10.1 mmol). The reaction mixture was stirred for 30 min.The mixture was partially concentrated to remove the MeOH. The resultingsolution was diluted with brine and extracted twice with DCM. Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated to give 66.3 mg of crude product which was used as is inthe subsequent step.Step F:

The aldehyde prepared as described in Step E immediately above (75 mg,0.29 mmol) was combined with 4-phenylpiperidine hydrochloride (116 mg,0.588 mmol), triethylamine (82 μL, 0.59 mmol), and sodiumtriacetoxyborohydride (312 mg, 1.47 mmol) in DCM (5 mL). The resultingmixture was stirred at room temperature overnight. The reaction mixturewas then diluted with DCM and washed with saturated NaHCO₃ solution,followed by brine, dried over anhydrous MgSO₄, filtered, andconcentrated. Purification by preparative TLC (silica, 0.35/3.15/96.5 ofNH₄OH/methanol/DCM) provided 74.1 mg of the desired product. ESI-MScalc. for C22H28N2O3S: 400; Found: 401 (M+H).Step G:

The aminoester product from Step F directly above (74 mg, 0.19 mmol) wasdissolved in 1:1 methanol/THF (2 mL). To it was added a solution ofLiOH.H₂O (15.5 mg, 0.370 mmol) in water (1 mL). The reaction mixture wasstirred at room temperature for 4.5 h, then was neutralized with 1.0 NHCl in ether (370 μL, 0.370 mmol) and concentrated. Purification bypreparative TLC (silica, 50% methanol/DCM) furnished 46.4 mg ofaminoacid.Step H:

The aminoacid prepared as described in Step G above (46.4 mg, 0.120mmol) was combined with 3,5-Bis(trifluoromethyl)benzylaminehydrochloride (67.1 mg, 0.240 mmol) and EDC (46.0 mg, 0.240 mmol) in DCM(2 mL). The reaction mixture was stirred at room temperature for 4 h,then was concentrated and applied directly to a preparative TLC plate(silica, 0.75/6.75192.5 of NH₄OH/methanol/DCM). After purification, 63mg of product were collected.

H NMR (CDCl₃, 500 4 MHz): δ 9.06 (s, 1H), 7.75 (s, 1H), 7.65 (s, 2H),7.29 (m, 3H), 7.17 (m, 3H), 6.63 (d, J=Hz, 1H), 6.56 (d, J=1.5 Hz,1H),4.51 (d, J=6 Hz, 2H), 3.68 (t, J=7 Hz, 1H), 3.01 (d, J=11.5 Hz, 1H),2.91 (d, J=11 Hz, 1H), 2.48 (m, 1H), 2.36 (m, 2H), 2.25 (m, 1H), 2.11(s, 3H), 1.93-2.08 (m, 3H), 1.82 (m, 2H), 1.68 (m, 2H).

ESI-MS calc. for C30H31F6N3O2S: 611; Found: 612 (M+H).

EXAMPLE 113

Step A:

5-Amino-3-methylisothiazole hydrochloride (25.0 g, 166 mmol) wasconverted to its free base by partitioning between DCM and 2 N NaOHsolution. The organic layer was dried over MgSO₄, filtered, andconcentrated giving 13.8 g of free base. To the free base was addedBOC₂O (70 g, 0.32 mol) and the mixture was warmed to 100° C. and stirredfor 23 h. The reaction mixture was cooled to room temperature and thevolatiles were removed under vacuum. The residue was purified by flashchromatography (silica, 20-40 gradient of ethyl acetate/hexane) toafford 21.3 g of product (82%). H NMR (CDCl₃, 500 MB): δ 7.76 (br s,1H), 6.43 (s, 1H), 2.37 (s, 3H), 1.53 (s, 9H).

ESI-MS calc. for C9H14N2O2S: 214; Found: 215 (M+H).Step B:

2.5 M n-butyl lithium (200 ml, 0.500 mol) was added to precooled (−78°C.) THF (100 mL) under N₂. By lowering bath attempted to controlreaction temperature at −70° C. while adding dropwise a solution ofN-t-butoxycarbonyl-5-amino-3-methylisothiazole hydrochloride (18.2 g,90.9 mmol) in THF (100 mL). After stirring an additional 0.5 h at −70°C., the reaction mixture was warmed to −30° C. and crushed dry ice (thensmall pieces, ˜50 g) was added (foaming-splashing). Then the reactionmixture was permitted to warm to room temperature and stir overnight.The reaction mixture was then partitioned between ethyl acetate and 2 NNaOH solution. The aqueous layer was made acidic (pH˜3) by dropwiseaddition of concentrated HCl solution with swirling. The aqueous mixturewas then extracted with ethyl acetate. The organic layer was dried overMgSO₄, filtered, and concentrated to give 6.37 g of product which wasused without further purification.

ESI-MS calc. for C10H14N2O4S: 258; Found: 259 (M+H).Step C:

The crude acid from Step C above (6.15 g, 23.8 mmol) was combined withmethanol (4.82 mL, 119 mmol), EDC (9.12 g, 47.6 mmol), and DMAP (145 mg,1.19 mmol) in DCM (100 mL). The resulting mixture was stirred at roomtemperature for 4 h, then was diluted with DCM (400 mL) and washed with1 N HCl solution (250 mL), water (250 mL), and brine (250 mL). Theorganic layer was dried over MgSO₄, filtered, and concentrated.Purification by MPLC (silica, 65% ethyl acetate/hexane) gave 1.27 g ofpure product.

H NMR (CDCl₃, 500 MHz): δ 7.66 (br s, 1H), 6.63 (s, 1H), 3.76 (s, 2H),3.72 (s, 3H), 1.53 (s, 9H).Step D:

A solution of the ester from Step C (996 mg, 3.66 mmol) in THF (30 mL)at −78° C. under nitrogen was treated dropwise with a 1.5M solution ofLDA.THF in cyclohexane (6.10 mL, 9.14 mmol). The mixture was stirred at−78° C. for 50 min, then was treated dropwise with allyl bromide (348μL, 4.03 mmol). After stirring at −78° C. for 2 h, then reaction mixturewas warmed to −10° C. (ice/salt bath) and stirred for 1 h. The reactionmixture was then warmed to room temperature, quenched by adding 10%citric acid solution, and partitioned between ethyl acetate and water.The organic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. Purification by MPLC (silica, 35%-65% ethyl acetate/hexanein 10% increments) provided 47 mg of the desired product.

H NMR (CDCl₃, 500 MHz): δ 8.04 (s, 1H), 6.64 (s, 1H), 5.73 (m, 1H),5.00-5.09 (m, 2H), 3.91 (t, J=7.5 Hz, 1H), 3.69 (s, 3E), 2.75-2.81 (m,1H), 2.61-2.66 (m, 1H), 1.51 (s, 9H).Step E:

The olefin from Step D above (46 mg, 0.15 mmol) was dissolved in 4:1acetone/water (2 mL) and treated with 1-methylmorpholine-N-oxide (21 mg,0.18 mmol), followed by a 4% aqueous solution of OsO₄ (47 μL, 0.0074mmol). The reaction mixture was stirred at room temperature for 2 h,then more 1-methylmorpholine-N-oxide (26 mg, 0.22 mmol) and 4% OsO₄ (50μL) was added. After 2 more h, the reaction mixture was partiallyconcentrated (at 16° C.) to remove the acetone. Ether was added and themixture was washed with 1N NaHSO₃ solution. The aqueous layer was backextracted twice with more ether and the combined ether extracts werewashed with brine, dried over MgSO₄, filtered, and concentrated. Theresulting crude diol (51 mg) was dissolved in 1:1 methanol/water (2 mL)and treated with NaIO₄ (47 mg, 0.22 mmol). The reaction mixture wasstirred for 0.5 h, then was partially concentrated to remove themethanol. The resulting aqueous mixture was partitioned between DCM andwater. The organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated to give 36.4 mg of the aldehyde, which wasused in Step F without further purification.Step F:

The aldehyde from Step E above (35 mg, 0.11 mmol) was combined withspiroindenepiperidine hydrochloride Intermediate 5 (52 mg, 0.22 mmol),triethylamine (31 μL, 0.22 mmol), and sodium triacetoxyborohydride (118mg, 0.555 mmol) in DCM (3 mL). The reaction mixture was stirred at roomtemperature for 30 min, then was diluted with DCM and washed withsaturated NaHCO₃ solution, followed by brine. The organic layer wasdried over MgSO₄, filtered, and concentrated. Purification bypreparative TLC (silica, 1/9/90 of NH₄OH/methanol/DCM) gave 45.2 mg ofdesired product.

ESI-MS calc. for C27H35N3O4S: 497; Found: 498 (M+H).Step G:

The aminoester from Step G above (43.5 mg, 0.0874 mmol) was dissolved in1:1 methanol/THF (2 mL) and treated with a solution of LiOH.H₂O (9.2 mg,0.22 mmol) in water (1 mL). The resulting mixture was stirred at roomtemperature for 16 h. The reaction mixture was quenched by addition of 1N HCl in ether (219 μL, 0.219 mmol) and concentrated. This crude mixturewas used as is in Step H below.

ESI-MS calc. for C26H33N3O4S: 483; Found: 484 (M+H).Step H:

The crude acid from Step G (ca. 42 mg, 0.087 mmol) was combined with3,5-Bis(trifluoromethyl)benzylamine hydrochloride (49 mg, 0.18 mmol),and EDC (34 mg, 0.18 mmol) in DCM (4 mL) and DMF (0.5 mL). The reactionmixture was stirred at room temperature for 5 h, then was concentratedto remove the DCM. The residue was diluted with ethyl acetate and washedwith saturated NaHCO₃ solution, water, and brine. The organic layer wasdried over anhydrous MgSO₄, filtered, and concentrated. Purification bypreparative TLC (silica, 0.8/7.2/92 of NH₄OH/methanol/DCM) afforded 51.3mg of the amide product.

ESI-MS calc. for C35H38F6N4O3S: 708; Found: 709 (M+H).Step I:

The Boc-aminoisothiazole from Step H (51 mg, 0.072 mmol) was dissolvedin 95% TFA/water (1 mL), stirred at room temperature for 45 min, thenconcentrated. Purification of the residue by preparative TLC (silica,0.8/7.2/92 of NH₄OH/methanol/DCM) gave 43.6 mg of product.

ESI-MS calc. for C30H30F6N40S: 608; Found: 609 (M+H).Step J:

The aminoisothiazole from Step I above (37.5 mg, 0.0616 mmol) wasdissolved in DCM (2 mL) and treated with pyridine (50 μL, 0.62 mmol),followed by acetic anhydride (58 μL, 0.62 mmol). The reaction mixturewas stirred overnight at room temperature. The reaction mixture wasconcentrated and the resulting residue was purified by preparative TLC(silica, 0.8/7.2/92 of NH₄OH/methanol/DCM). The product was converted toits hydrochloride salt by dissolving in DCM (1 mL) and adding an excessof 1 M HCl in ether (˜100 μL), then concentrating to give a white solid(25.5 mg).

ESI-MS calc. for C32H32F6N4O2S: 650; Found: 651 (M+H).

EXAMPLE 114

Step A:

Concentrated H₂SO₄ (24.5 g, 0.250 mol) was added dropwise at a rapidrate to a suspension of MgSO₄ (120 g, 1.00 mol) in DCM (11). The mixturewas stirred magnetically overnight, however the next morning it wasevident that solids prevented adequate stirring so a mechanical overheadstirring system was installed. 4-penteneoic acid (25 g, 0.25 mol) wasadded, followed by t-butanol (92.5 g, 1.25 mol). The mixture was stirredat rt for 4 days, upon which time TLC indicated that some startingmaterial remained. None-the-less the reaction mixture was filteredthrough celite and washed with saturated NaHCO₃ solution (gasevolution). The aqueous layer was back extracted with DCM and thecombined organic layers were then washed with saturated NaHCO₃ solution,twice with water, and with brine. The organic layer was dried overanhydrous MgSO₄, filtered, and concentrated. Flash chromatography(silica, 15% ether/pentane) afforded 19.6 g of pure ester (50% yield).

H NMR (CDCl₃, 500 MHz): δ 5.82 (m, 1H), 4.98-5.07 (m, 2H), 2.32 (m, 4H),1.44 (s, 9H).Step B:

Threo product: t-Butyl-4-pentenoate prepared as described in theprevious step (2.00 g, 12.8 mmol) was added in THF (10 mL) over 2-3 minto LDA (1.5 M in cyclohexane, 10.3 mL, 15.4 mmol) in THF (30 mL)precooled to −78° C. and under an N₂ atmosphere. The mixture was stirredat −78° C. for 0.5 h, then commercially available methyl4-bromocrotonate (2.52 g, 14.1 mmol) in THF (10 mL) was added dropwise.The reaction mixure was allowed to slowly warm to rt and stir overnight.The reaction mixture was then poured into brine, and extracted twicewith ether. The combined ethereal layers were dried over anhydrousMgSO₄, filtered, and concentrated. Purification by MPLC (silica, 15%ethyl acetate/hexane) provided 0.980 g of product, which by literatureprecedent was presumed to be threo, with trans substitution on thecyclopropyl ring.

H NMR (CDCl₃, 500 MHz): δ 5.77 (m, 1H), 5.01-5.10 (m, 2H), 3.66 (s, 3H),2.45 (m, 0.1H), 2.33 (m, 1H), 1.75 (m, 1H), 1.63 (m, 1H), 1.53 (m, 1H),1.43 (s, 9H), 1.25 (m, 1H), 0.77 (m, 1H[). Erythro product: To asolution of LDA (1.5 M in cyclohexane, 28.3 mL, 42.4 mmol) in a mixtureof THF (60 mL) and HMPA (25 mL) under an N₂ atmosphere at −78° C. wasadded dropwise over 10 min t-Butyl-4-pentenoate prepared as described instep A (5.52 g, 35.3 mmol) in THF (20 mL). The reaction mixture wasstirred at −78° C. for 30 min, then methyl 4-bromocrotonate (6.95 g,38.8 mmol) in THF (20 mL) was added dropwise over 10 min. The resultingreaction mixture was stirred at −78° C. for 1 h, then was warmed to rtand stirred overnight. The reaction mixture was poured into water andextracted twice with ether. The combined ethereal layers were washedfive times with water, and once with brine, dried over anhydrous MgSO₄,filtered, and concentrated. Purification by MPLC (silica, 15% ethylacetate/hexane) afforded 2.39 g of product, which by literatureprecedent was assumed to be erythro, with trans substitution on thecyclopropyl ring.

H NMR (CDCl₃, 500 MHz): δ 5.75 (m, 1H), 5.00-5.08 (m, 2H), 3.67 (s, 3H),2.46 (m, 1H), 2.33 (m, 1H), 1.75 (m, 1H), 1.56 (m, 1H), 1.47 (obscuredm, 1H), 1.44 (s, 9H), 1.20 (m, 1H), 0.93 (m, 1H).Step C:

Threo isomer: The threo diester prepared as described in Step B (2.77 g,10.9 mmol) was treated with TFA (20 mL), stirred at room temperature forone h, then concentrated to give 2.60 g of crude product, which was usedas is in Step D.

Erythro isomer: The erythro diester was deprotected in an identicalfashion to that described for the threo isomer immediately above.Step D:

Threo isomers: The threo carboxylic acid prepared as described in Step C(10.4 mmol) was combined with 3,5-Bis(trifluoromethylbenzylaminehydrochloride (5.82 g, 20.8 mmol), HOAt (2.83 g, 20.8 mmol), and DIEA(4.63 mL, 26.0 mmol) in DCM (80 mL) and the resulting mixture was cooledto 0° C. EDC (3.99 g, 20.8 mmol) was added and the reaction mixture waspermitted to warm to rt and stir for 2.5 h. The reaction mixture wasdiluted with DCM and washed with water, 1 N HCl solution, saturatedNaHCO₃ solution, and brine. The organic layer was dried over anhydrousMgSO₄, filtered, and concentrated. The product was clean by H NMR andwas used without further purification in Step E.

H NMR (CDCl₃, 500 MHz): δ 7.90 (s, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 5.73(m, 1H), 5.04 (app dq, J=1.5, 17 Hz, 1H), 4.96 (m, 1H), 4.56 (d, J=15.5Hz, 1H), 4.45 (d, J=16 Hz, 1H), 3.59 (s, 3H), 2.48 (m, 1H), 2.35 (m,1H), 1.80 (m, 1H), 1.58 (m, 2H), 1.19 (m, 1H), 0.86 (m, m).

Erythro isomers: The erythro amides were prepared in the same fashion asdescribed for the synthesis of the threo amides immediately above.

H NMR (CDCl₃, 500 MHz): δ 7.90 (s, 1i), 7.87 (s, 1H), 7.85 (s, 1H), 5.73(m, 1H), 5.03 (m, 1H), 4.96 (m, 1H), 4.55 (d, J=15.5 Hz, 1H), 4.48 (d,J=16 Hz, 1H), 3.65 (s, 3H), 2.48 (m, 1H), 2.34 (m, 1H), 1.81 (m, 1H),1.56 (m, 2n), 1.11 (m, 1H), 0.93 (m, 1H).Step E:

Threo diastereomers: Ozone gas was bubbled through a precooled solutionof the threo amide prepared as described in Step D (10 mmol) in DCM (75mL) at −78° C. until a blue color persisted. N₂ was then bubbled throughthe solution until the blue color has disappeared. The solution wasdried over MgSO₄, filtered, and concentrated to a volume ofapproximately 40 mL. To the resulting aldehyde was added a solution of3-methyl-4-spiroindenylpiperidine hydrochloride (Intermediate 5, 2.83 g,12.0 mmol) and triethylamine (1.67 mL, 12.0 mmol) in DCM (15 mL).Approximately 5 g of 4° A molecular sieves (powder) was added. Thensodium triacetoxyborohydride (7.42 g, 35.0 mmol) was added and thereaction mixture was stirred at rt for 21.5 h. The reaction mixture wasthen diluted with DCM and filtered through a celite plug. The filtratewas washed with saturated NaHCO₃ solution, water, and brine, dried overanhydrous MgSO₄, filtered and concentrated. Two successive purificationsby flash chromatography (silica, 5% of (10% NH₄OH/MeOH) in DCM) gave1.90 g of product.

ESI-MS calc. for C32H34F6N2O3: 608; Found: 609 (M+H).

Erythro diastereomers: The erythro target compounds were prepared fromthe erythro olefin prepared as described in Step D (9.5 mmol) in exactlythe same fashion as the threo compounds described immediately above togive 964 mg of desired product.

ESI-MS calc. for C32H34F6N2O3: 608; Found: 609 (M+H).

Single isomers of substituted cyclopropyl compounds can be prepared byresolution intermediate from Step B of Example 114 using a chiraloxazolidinone auxiliary. See for example resolution of the erythroisomers:Step B1:

A solution of the diester from Step B above (erythro, 17.3 g, 68.0 mmol)in 200 mL of 1:1 THF/methanol was treated with a solution of LiOH.H₂O(14.3 g, 340 mmol) in 100 mL of water. The reaction mixture was stirredat room temperature for 3 h, then was quenched with excess 10% citricacid. The mixture was extracted with ethyl acetate and the organic layerwas washed with 1 N HCl solution and brine, dried over anhydrous MgSO₄,filtered, and concentrated. Purification by flash chromatography(silica, 1-5% stepwise gradient methanol/DCM) afforded 13.0 g (80%) ofacid.

H NMR (CDCl₃, 500 z): δ 5.78 (m, 1H), 5.08 (m, 2H), 2.48 (m, 1H), 2.37(m, 1H), 1.78 (m, 1H), 1.65 (m, 1H), 1.47 (s, 9H), 1.46 (obsc m, 1H),1.28 (m, 1H), 1.02 (m, 1H).Step B2:

To a solution of the erythro carboxylic acid prepared as described inStep B1 (13.0 g, 54.2 mmol) in THP (50 mL) at 0° C. under an N₂atmosphere was added dropwise DIEA (9.42 mL, 54.2 mmol), followed bypivaloyl chloride (6.64 mL, 54.2 mmol). In a separate vessel, aprecooled (−78° C.) solution of (R)-(+)-4-benzyl-2-oxazolidinone (9.59g, 54.2 mmol) in THF (50 mL) under an N₂ atmosphere was treated dropwisewith n-butyl lithium in hexane (1.6 M, 33.9 mL, 54.2 mmol). Bothsolutions were stirred for approximately 30 min, at which time thesolution of oxazolidinone anion was transferred by cannula to thepreformed mixed anhydride. The resulting reaction mixture was permittedto warm to rt and stir overnight. The reaction mixture was diluted withethyl acetate and washed with 1 N HCl solution, saturated NaHCO₃solution, and brine (each time back extracting with more ethyl acetate).The organic layer was dried over anhydrous MgSO₄, filtered, andconcentrated. The crude product was purified by MPLC (silica, 30% ethylacetate/hexane) whereupon the two erythro diastereomers separated togive single diastereomers: 4.5 g of the higher band isomer and 6.0 g ofthe lower band isomer, as well as an additional 3.1 g of mixed isomers(total yield 63%).

Higher band: H NMR (CDCl₃, 400 M}): δ 7.2-7.38 (m, 5H), 5.78 (m, 1H),4.99-5.08 (m, 2H), 4.69 (m, 1H), 4.20 (m, 2H), 3.28 (dd, J=3.3, 13.5 Hz,1H), 3.11 (m, 1H), 2.77 (dd, J=5.7, 13.3 Hz, 1H), 2.48 (m, 1H), 2.39 (m,1H), 1.91 (m, 1H), 1.72 (m, 1H), 1.48 (s, 9H), 1.44 (obsc m, 1H), 1.14(m, 1H).

Lower band: H NMR (CDCl₃,400 MHz): δ 7.21-7.36 (m, 5H), 5.82 (m, 1H),5.07 (m, 2H), 4.68 (m, 1H), 4.20 (m, 2H), 3.25 (dd, J=3.2, 13.2 Hz, 1H),3.10 (m, 1H), 2.82 (dd, J=9.2, 13.2 Hz, 1H), 2.54 (m, 1H), 2.45 (m, 1H),1.92 (m, 1H), 1.74 (m, 1H), 1.48 (s, 9H), 1.43 (m, 1H), 1.11 (m, 1H).Step B3:

A solution LiOH.H₂O (1.04 g, 24.8 mmol) in water (60 mL) was added to aprecooled (0° C.) mixture of 30% hydrogen peroxide solution (5.06 mL,49.5 mmol) in THF (40 mL). Then a solution of the higher band erythroacyloxazolidinone prepared as described in Step B2 (4.95 g, 12.4 mmol)in THF (80 mL) was added dropwise. The reaction mixture was stirred at0° C. for 40 min, then was quenched by addition of saturated Na₂SO₃solution (40 mL), followed by saturated NaHCO₃ solution (40 mL). Theresulting mixture was extracted three times with ethyl acetate to removethe chiral auxiliary. The aqueous layer was adjusted to pH˜4 with 1 NHCl and then extracted six times with chloroform. The combined organiclayers were dried over anhydrous MgSO₄, filtered, and concentrated togive 1.79 g (60%) of carboxylic acid as a single isomer. Note that thelower band erythro acyloxazolidinone could be hydrolyzed in an identicalfashion (64% yield).

Higher band erythro acid: H NMR (CDCl₃, 500 MHz): δ 5.78 (m, 1H),5.04-5.12 (m, 2H), 2.49 (m, 1H), 2.37 (m, 1H), 1.79 (m, 1H), 1.65 (m,1H), 1.48 (obsc. M, 1H), 1.47 (s, 9H), 1.29 (m, 1H), 1.03 (m, 1H).

Lower band erythro acid: H NMR (CDCl₃, 500 MHz): δ 5.79 (m, 1H),5.04-5.12 (m, 2H), 2.48 (m, 1H), 2.38 (m, 1H), 1.78 (m, 1H), 1.65 (m,1H), 1.48 (obsc. M, 1H), 1.47 (s, 9H), 1.28 (m, 1H), 1.02 (m, 1H).

Note that acids resolved as described immediately above could be used toprepare a variety of isomerically pure CCR-2 antagonists by integratingthem into syntheses such as shown in Example 114, as well as examplesthat follow.

EXAMPLE 115

To a solution of the amino ester prepared as described in Example 114(threo, 1.87 g, 3.06 mmol) in 12 mL of 1:1 THF/methanol was added asolution of LiOH.H₂O (385 mg, 9.17 mmol) in water (6 mL). The resultingmixture was stirred at rt for 5 h, then quenched by addition of 4 N HClin dioxane (2.3 mL, 9.2 mmol). The reaction mixture was concentrated andpurified by flash chromatography (silica, 25% methanol/DCM followed by50% methanol/DCM) to give 1.90 g of product.

ESI-MS calc. for C31H32F6N2O3: 594; Found: 595 (M+H).

This same procedure was carried out on the erythro isomers.

EXAMPLE 116

To a solution of the acid prepared as described in Example 115 (threo,406 mg, 0.683 mmol) in, THF (6 mL) at 0° C. was added N-methylmorpholine(76 mg, 0.75 mmol) followed by i-butylchloroformate (103 mg, 0.751mmol). The reaction mixture was stirred at 0° C. for 40 min, then wastreated with a solution of sodium borohydride (41 mg, 1.09 mmol) inwater (1 mL), whereupon gas evolution was observed. After 15 min at 0°C. the reaction mixture was diluted with ethyl acetate and washed withsaturated NaHCO₃ solution and brine, dried over anhydrous MgSO₄,filtered, and concentrated. Purification by preparative TLC (silica, 7%of 1:9 NH₄—OH/methanol in DCM) gave 77 mg of alcohol.

ESI-MS calc. for C31H34F6N2O2: 580; Found: 581 (M+H).

EXAMPLE 117

Step A:

To a solution of the threo alcohol prepared as described in Example 116(73.7 mg, 0.127 mmol) and N-methylmorpholine (19.3 mg, 0.191 mmol) inDCM (4 mL) at 0° C. was added methanesulfonyl chloride (17.5 mg, 0.152mmol). The reaction mixture was placed in the freezer (˜−20° C.) forovernight. The reaction mixture was diluted with DCM and washed withwater twice, saturated NaHCO₃ solution, and brine, dried over anhydrousMgSO₄, filtered, and concentrated. The resulting crude mesylate wasdissolved in DMF (4 mL) and treated with NaN₃ (25 mg, 0.38 mmol). Thetemperature was raised to 50° C., stirred for 3.5 h, then cooled to rtand left over the weekend. The reaction mixture was diluted with ethylacetate and washed with water. The aqueous layer was back-washed withethyl acetate. The combined organic layers were then washed with waterand brine, dried over anhydrous MgSO₄, filtered, and concentrated.Purification by preparative TLC (silica, 5% of 1:9 NH4OH/methanol inDCM) gave 50 mg of azide product.

ESI-MS calc. for C31H33F6N5O: 605; Found: 606 (M+H).Step B:

To a solution of the threo azide prepared as described in Step A (50 mg,0.083 mmol) in THF (3 mL) was added triphenylphosphine (32 mg, 0.12mmol). The mixture was stirred at rt for 30 min, then water was added (1mL) and the mixture was stirred for overnight. The next day, thereaction had proceeded very little, so an additional amount oftriphenylphosphine (217 mg, 0.826 mmol) was added, as well as 1 mL ofwater. After stirring overnight, the reaction mixture was concentratedand purified by preparative TLC (silica, 10% of 1:9 NH₄OH/methanol inDCM) to give 37 mg of amine. ESI-MS calc. for C31H35F6N3O: 579; Found:580 (M+H).

EXAMPLE 118

Step A:

A solution of the diester from Step B Example 114 above (threo, 6.59 g,25.9 mmol) in 50 mL of 1:1 THF/methanol was treated with a solution ofLiOH.H₂O (5.44 g, 130 mmol) in 25 mL of water. The reaction mixture wasstirred at room temperature for 5 h, then was partially concentrated toremove the organic solvents. The mixture was treated with excess 1 N HClsolution to make the pH acidic and was extracted twice with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous MgSO₄, filtered, and concentrated to give 5.94 g of acid.Step B:

The threo acid prepared as described in Step A (4.92 g, 20.5 mmol) wascombined with diphenylphosphoryl azide (4.86 mL, 22.6 mmol) andtriethylamine (3.43 mL, 24.6 mmol) in toluene (30 mL) and stirred at 90°C. for 2 h. t-Butanol (40 mL) was then added and the reaction mixturewas stirred at 90° C. for an additional 8 h. The reaction mixture wasconcentrated, redissolved in ether, and washed successively with 1 NHCl, saturated NaHCO₃ solution, and brine. The organic layer was driedover anhydrous MgSO₄, filtered, and concentrated. Purification by MPLC(silica, 25% ethyl acetate/hexane) provided 4.77 g of the t-butylcarbamate (75%).

H NMR (CDCl₃, 500 MHz): δ 5.76 (m, 1H), 5.00-5.09 (m, 2H), 4.66 (br s,1H), 2.49 (m, 1H), 2.39 (m, 1H), 2.32 (m, 1H), 1.77 (m, 1H), 1.45 (s,9H), 1.43 (2 overlapping s, 9H, rotameric BOC), 1.03 (m, 1H), 0.78 (m,1H), 0.63 (m, 1H).Step C:

Ozone was bubbled through a cooled (−78° C.) solution of the t-butylcarbamate prepared as described in Step B (3.53 g, 11.3 mmol) until ablue color persisted. N₂ Gas was bubbled through the solution until theblue color had disappeared. Triphenylphosphine (3.26 g, 12.4 mmol) wasadded and the reaction mixture was allowed to warm to rt and stir for2.5 h. The reaction mixture was concentrated. To the residue was added55% ethyl acetate/hexane and the mixture was filtered to removeinsoluble triphenylphosphine oxide. The filtrate was concentrated andpurified by MPLC (silica, 55% ethyl acetate/hexane) to afford 1.84 g ofaldehyde. The aldehyde (1.17 g, 3.73 mmol) was combined with3-methyl-4-spiroindenylpiperidine hydrochloride (Intermediate 5, 880 mg,3.73 mmol) and triethylamine (0.52 mL, 3.7 mmol) in DCM (15 mL). Thensodium triacetoxyborohydride (2.77 g, 13.1 mmol) was added and thereaction mixture was stirred at rt for 2 h. The reaction mixture wasthen diluted with DCM and washed with saturated NaHCO₃ solution, water,and brine, dried over anhydrous MgSO₄, filtered and concentrated.Purification by MPLC (silica, 80% ethyl acetate/hexane, then ethylacetate) gave 1.53 g of threo amine product.Step D:

The aminoester prepared as described in Step C (1.46 g, 2.94 mmol) wasdissolved in 1:1 TFA/DCM (20 mL) and stirred at room temperature for 3h. The reaction mixture was concentrated, then redissolved inmethanol/toluene and concentrated twice to remove some of the remainingTFA and providing 1.98 g of crude product (still contaminated with TFA).

ESI-MS calc. for C21H28N2O2: 340; Found: 341 (M+H).Step E:

To a solution of the threo diaminoacid prepared as described in Step D(˜2.9 mmol) in water (15 mL) was added a solution of NaOH (661 mg, 16.5mmol) in water (10 mL) until the pH was 9. Then dioxane (10 mL) wasadded, followed by BOC₂O (1.27 g, 5.80 mmol) in dioxane (5 mL). Thereaction mixture was stirred overnight, then neutralized with 1 N HCl,and concentrated. The residue was purified by flash chromatography(silica, 10-20% methanol/DCM stepwise gradient) to afford 1.47 g ofproduct.

ESI-MS calc. for C26H36N2O4: 440; Found: 441 (M+H).Step F:

The BOC-aminoacid prepared as described in Step E (˜2.6 mmol) wascombined with 3,5-Bis(trifluoromethyl)benzylamine hydrochloride (1.47 g,5.24 mmol) and HOAt (0.702 g, 5.24 mmol) in DCM (15 mL) and theresulting mixture was cooled to 0° C. EDC (1.01 g, 5.24 mmol) was addedand the reaction mixture was stirred at 0° C. for 1.5 h, then warmed tort and stirred for an additional 1.75 h. The reaction mixture wasdiluted with DCM and washed with water, 1 N HCl solution, saturatedNaHCO₃ solution, and brine. The organic layer was dried over anhydrousMgSO₄, filtered, and concentrated. Purification by MPLC (silica, 10%methanol/ethyl acetate) gave 1.21 g of desired amide.

ESI-MS calc. for C35H41F6N3O3: 665; Found: 666 (M+H).Step G:

The threo BOC-amide prepared as described in Step F (1.15 g, 1.73 mmol)was dissolved in 4 N HCl in dioxane (25 mL), stirred for 3 h, andconcentrated to give 1.25 g of crude product as its Bis-hydrochloridesalt.

ESI-MS calc. for C30H33F6N3O: 565; Found: 566 (M+H).

The products from Examples 115-118 can themselves serve as intermediatesfor the synthesis of a variety of CCR-2 antagonists by forming amides,sulfonamides, carbamates, ureas, heterocycles, etc, using standardchemistry known to those skilled in the art. These compounds can beprepared as diastereomeric mixtures or as single diastereomers (byresolution of the final compounds by chiral HPLC or by use of opticallypure building blocks for the synthesis-see Example 114). The followingtable lists some representative examples of compounds prepared using thetitle compounds from Examples 115-118 as intermediates. TABLE

ESI-MS found Example R group Calc. MW (M + H)⁺ 119 CONHEt 621 622 120NHCO₂Me 623 624 121 NHAc 607 608 122 NHCOPh 669 670 123 NHCOCH₂NH₂ 622623 124

670 671 125 NHSO₂Me 643 644 126 NHSO₂NMe₂ 672 673 127 NHSO₂NHCO₂Et 716717 128 NHSO₂Ph 705 706 129 NHCONH₂ 608 609 130 NHCONHMe 622 623 131NHCONMe₂ 636 637 132

678 679 133

617 618 134

631 632 135 CH₂NHAc 621 622 136 CH₂NHCOPh 683 684 137 CH₂NHCOCH₂NH₂ 636637 138 CH₂NMe2 607 608 139 CH₂NH-i-Pr 621 622 140 CH₂NHSO₂Me 657 658141 CH₂NHSO₂CF₃ 711 712 142 CH₂NHSO₂-i-Pr 685 686 143 CH₂NHSO₂Et 671 672144 CH₂NHSO₂-n-Pr 685 686 145 CH₂NHSO₂-i-Bu 699 700 146 CH₂NHSO₂Ph 719720 147 CH₂NHSO₂NMe₂ 686 687 148 CH₂NHCONH₂ 622 623 149 CH₂NHCONHMe 636637 150 CH₂NHCONMe₂ 650 651 151 CH₂NHCONHEt 650 651 152 CH₂NHCONHPh 698699 153 CH₂NHCONH-t-Bu 677 678 154 CH₂NHCONH-n-Bu 677 678 155CH₂NHCONH-cyclopropyl 662 663 156 CH₂NHSO₂NHCO₂Et 730 731 157 CH₂NHCO₂Me637 638 158 CH₂OCONHEt 651 652 159

692 693

Intermediate 47

Step A

To a solution of lithium bis(trimethylsilyl)amide, LHMDS, (5.69 g, 34.0mmol) in THF (50 ml) cooled to −78° C. by dry ice/acetone bath was addedmethoxyacetic acid (2.27 ml, 29.58 mmol) in 20 ml THF via syringe andthe resulting mixture stirred for one hour. The mixture was treated with2,2-dimethyoxy, 1-bromoethane (5 g, 29.58 mmol) and stirred overnightallowing to warm to room temperature. The reaction was quenched with asaturated solution of ammonium chloride (50 ml) and the resultingmixture was poured into a separatory funnel. The organic layer wasseparated, washed with brine (1×25 mL), dried with anhydrous sodiumsulfate and the solvent was evaporated in vacuo to yield 2.16 g (41%) ofthe crude product. The crude residue was passed through a small plug ofsilica gel (eluant 60% ethyl acetate/hexane) to remove polar impuritiesto yield 1.69 g (32%) of the racemic desired product. ¹H NMR (400 MHz,CDCl₃): 4.59 (dd, J=5.1, 6.6 Hz, 1H), 3.88 (dd, J=4.5, 6.7, 1H), 3.46(s, 3H), 3.33 (s, 3H), 3.31 (s, 3H), 2.15-2.07 (m, 11), 2.05-1.98 (m,1H).Step B

A mixture of the acid (described in step A, 64 mg, 0.54 mmol),3,5-bis(trifluoromethyl)benzylamine hydrochloride (151 mg, 0.54 mmol),HOBt (73 mg, 0.54 mmol), N,N-diisopropyl ethylamine (94 μl, 0.54 mmol)in dichloromethane (3 mL) was treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 208mg, 1.08 mmol) and stirred at room temperature overnight. The reactionmixture was diluted with dichloromethane (7 mL), washed with water (2×5mL), brine (1×5 mL), dried over anhydrous sodium sulfate and the solventwas evaporated. Purification was done by preparative TLC (eluent: 30%ethyl acetate/hexane) to yield 157 mg (72%) of the desired product.LC-MS for C₁₆H₁₉NO₄F₆ [M+H]⁺ calculated 403.16, found 404.

EXAMPLE 160

Intermediate 47 (50 mg, 0.134 mmol) was treated with a solution of 90%trifluoroacetic acid/water (1 ml) for 10 minutes. The reaction mixturewas diluted with water (2 mL) and extracted with ether (3×10 ml). Theorganic layers were combined, washed with saturated sodium bicarbonate(3×3 mL), brine (1×5 mL), dried over anhydrous sodium sulfate and thesolvent was evaporated in vacuo to yield 45 mg (96%) of the crudeproduct.

A solution of the above crude product (45 mg, 0.129 mmol),spiroindenylpiperidine hydrochloride (30 mg, 0.134 mmol),diisopropylethylamine (24 μL, 0.134 mmol) and crushed molecular sieves(4A, 25 mg) in dichloroethane (2 mL) was treated with sodiumtriacetoxyborohydride (143 mg, 0.134 mmol) and stirred at roomtemperature overnight. The sieves were filtered off (plug of Celite),washed with dichloromethane and the combined organic washings wereextracted with a saturated solution of sodium bicarbonate (1×5 mL),brine (1×5 mL) and dried over anhydrous sodium sulfate. Solvent wasevaporated to dryness and the residue was purified by preparative TLC(eluent: 5% methanol/95% ethyl acetate) to yield 30.1 mg (41%) of thefinal pure desired product. ¹H NMR (400 MHz, CD₃OD): 7.94 (s, 2H), 7.83(s, 1H), 7.36-7.34 (m, 2H), 7.27-7.23 (m, 2H), 7.00 (d, J=5.7 Hz, 1H),6.90 (d, J=5.5 Hz, 1H), 4.58 (ABq, J=4.6 Hz, 2), 3.94 (dd, J=4.8, 6.6Hz, 1H), 3.74-3.65 (m, 2H), 3.47 (s, 3H), 3.37-3.29 (m, 41), 2.43 (br t,J=4.6 Hz, 1H), 2.36-2.25 (m, 1H), 2.23-2.14 (m, 1H). 1.50 (br d, J=4.6Hz, 1H), 1.37-1.28 (m, 2H). LC-MS for C₂₇H₂₈N₂OF₆ [M+H]⁺ calculated526.21, found 527.

EXAMPLE 161

Step A

A solution of methyl 2-aminobutenoate (2.32 g, 17.96 mmol) and phthalicanhydride (2.96 g, 20 mmol) in toluene (60 mL) was heated with stirringto reflux for 6 hrs. The reaction solvent was evaporated, and theresidue was recrystallized from diethyl ether hexane (1:1) mixture toyield 4.20 g (90%) of the pure product. ¹H NMR (CDCl₃): 7.87 (m, 2H),7.75 (m, 2H), 5.74 (m, 1H), 5.08 (ddd, J=17.2, 3.0, 1.4 Hz, 1H), 5.00(dd, J=10.3, 0.9 Hz, 1H), 4.96 (dd, J=9.2, 6.6 Hz, 1H), 3.77 (s, 3H),3.00 (m, 2H).Step B

A solution of the olefin from previous step (910 mg, 3.4264 mmol) indichloromethane (30 mL) was cooled to −78° C. and ozone was passedthrough until a permanent blue color indicated consumption of theolefin. Excess ozone was purged with nitrogen, and 3 mL of dimethylsulfide was added. Cooling bath was removed, and the reaction mixturewas allowed to warm up to room temperature. The solvent was removed invacuo and the crude aldehyde was dissolved in dichloroethane (20 mL).4-Spiroindenyl piperidine hydrochloride (772 mg, 3.4822 mmol),diisopropylethylamine (600 μL, 3.4822 mmol) and finally sodiumtriacetoxyborohydride (3.70 g, 17.4 mmol) were added and the reactionmixture was stirred at room temperature overnight. It was diluted withdichloromethane (100 mL) and extracted with water (2×50 mL), dried withanhydrous sodium sulfate and evaporated to dryness. The crude product(1.60 g, 100%) was taken into the next step without additionalpurification. MS: for C₂₆H₂₆N₂O₄ [M+H]⁺ calculated: 431.19, found 431.0.Step C

A solution of the crude product from previous step (1.60 g, 3.4264 mmol)in dioxane (30 mL) was treated with aqueous solution of lithiumhydroxide (1N, 12.0 mL) and stirred at room temperature for 1 hr. 6.0 mLof 2N HCl was added to neutralize the lithium hydroxide, and thereaction mixture was evaporated to dryness.

The crude product (containing lithium chloride) was suspended indichloromethane, 3,5-bistrifluoromethylbenzylamine hydrochloride (958mg, 3.4264 mmol), diisopropylethylamine (1.19 mL, 6.8528 mmol),1-hydroxy-7-azabenzotriazole (466 mg, 3.4264 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 985mg, 5.1396 mmol) were added and the reaction mixture was stirred at roomtemperature overnight. It was diluted with dichloromethane, washed withwater. After drying with anhydrous sodium sulfate the solvent wasevaporated to dryness, and the residue was purified by flashchromatography (ethyl acetate hexanes/7:3) to yield 244 mg (10%) of thepure product. MS: for C₃₄H₂₉N₂O₄F₆ [M+H]⁺ calculated: 642.21, found642.4.

EXAMPLE 162

A solution of the phthalimide, preparation of which was described inExample 161(216 mg, 0.3367 mmol) in ethyl alcohol (15 mL) was treatedwith hydrazine (100 μL) and heated to reflux for 60 minutes. Thereaction mixture was allowed to cool down to ambient temperature and theprecipitate of the phthalic hydrazide was filtered off. The filtrate wasevaporated to dryness, the remaining solid was boiled briefly withdiethyl ether and filtered again. The filtrate was evaporated to drynessto leave after its conversion to the respective dihydrochloride 204 mgof the pure product. MS: for C₂₆H₂₇N₃OF₆ [M+H]⁺ calculated: 512.21,found 512.30.

EXAMPLE 163

A solution of the primary amine hydrochloride described in Example 162(12 mg, 0.0219 mmol), diisopropylethylamine (12 μL, 0.0657 mmol) indichloromethane (2 mL) was treated with methanesulfonyl chloride (2 μL,0.026 mmol) and stirred at room temperature for 1 hr. Water (2 mL) wasadded and the organic layer was separated. It was washed with water 2more times, finally with brine. After drying with anhydrous sodiumsulfate the solvent was evaporated to leave 9.0 mg (66%) of pureproduct. MS: for C₂₇H₂₉N₃O₃SF₆ [M+H]⁺ calculated: 590.18, found 590.30.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A compound of the formula I:

W is selected from the group consisting of: C, N, and —O—, wherein whenW is N, then R⁴ is absent, and when W is —O—, then both R³ and R⁴ areabsent; X is selected from the group consisting of: —NR¹⁰—, —O—, —CH₂O—,—CONR¹⁰—, —NR¹⁰CO—, —CO₂—, —OCO—, —CH₂(NR¹⁰)CO—, —N(COR¹⁰)—, and—CH₂N(COR¹⁰)—, and where R¹⁰ is independently selected from: hydrogen,C₁₋₆ alkyl, benzyl, phenyl, and C₁₋₆ alkyl-C₃₋₆ cycloalkyl, which isunsubstituted or substituted with 1-3 substituents where thesubstituents are independently selected from: halo, C₁₋₃alkyl,C₁₋₃alkoxy and trifluoromethyl; or where R¹⁰ and R² may be joinedtogether to form a 5- or 6-membered ring, R¹ is selected from: hydrogen,—C₀₋₆alkyl-Y-phenyl-, —C₀₋₆alkyl-Y-heterocycle-,—C₀₋₆alkyl-Y—(C₀₋₆alkyl)-, and—(C₀₋₆alkyl)-Y-(C₀₋₆alkyl)-(C₃₋₇cycloalkyl)-(C₀₋₆alkyl), where Y isselected from: a single bond, —O—, —S—, —SO—, —SO₂—, and —NR¹⁰—, andwhere the phenyl, heterocycle, alkyl and the cycloalkyl areunsubstituted or substituted with 1-7 substituents where thesubstituents are independently selected from: (a) halo, (b) hydroxy, (c)—O—C₁₋₃alkyl, (d) trifluoromethyl, (e) C₁₋₃alkyl, (f) —C₃₋₆cycloalkyl(g) —CO₂R⁹, wherein R⁹ is independently selected from: hydrogen, C₁₋₆alkyl, C₅₋₆ cycloalkyl, benzyl or phenyl, which is unsubstituted orsubstituted with 1-3 substituents where the substituents areindependently selected from: halo, C₁₋₃alkyl, C₁₋₃alkoxy andtrifluoromethyl, (h) —CN, (i) —NR⁹R¹⁰, (j) —NR⁹COR¹⁰, (k) —NR⁹SO²R¹⁰,(l) —NR⁹CO₂R¹⁰, (m) —NR⁹CONR⁹R¹⁰, (n) —CONR⁹R¹⁰, (o) heterocycle, (p)phenyl; R² is selected from: (C₀₋₆alkyl)-phenyl and(C₀₋₆alkyl)-heterocycle, where the alkyl is unsubstituted or substitutedwith 1-7 substituents where the substituents are independently selectedfrom: (a) halo, (b) hydroxy, (c) —O—C₁₋₃alkyl, (d) trifluoromethyl, (e)—C₁₋₃alkyl, (f) —CO₂R⁹, and (g) oxo; and where the phenyl and theheterocycle may be unsubstituted or substituted with 1-5 substituentswhere the substituents are independently selected from: (a) halo, (b)trifluoromethyl, (c) trifluoromethoxy, (d) hydroxy, (e) C₁₋₆alkyl, (f)C₃₋₇cycloalkyl, (g) —O—C₁₋₆alkyl, (h) —O—C₃₋₇cycloalkyl, (i) —SCF₃, (j)—S—C₁₋₆alkyl, (k) —SO₂—C₁₋₆alkyl, (l) phenyl, (m) heterocycle, (n)—CO₂R⁹, (o) —CN, (p) —NR⁹R¹⁰, (q) —NR⁹—SO₂—R¹⁰, (r) —SO₂—NR⁹R¹⁰, (s)—CONR⁹R¹⁰, and (t) —O-phenyl; R³ is selected from: hydrogen,(C₀₋₆alkyl)-phenyl, (C₀₋₆alkyl)-heterocycle, —C₁₋₆alkyl, CF₃,C₃₋₇cycloalkyl, —NR⁹R¹⁰, —CO₂R⁹, —NR⁹—SO₂—R¹⁰, —NR⁹CONR⁹R¹⁰, and—CONR⁹R¹⁰, where the alkyl is unsubstituted or substituted with 1-5substituents where the substituents are independently selected from: (a)halo, (b) hydroxy, (c) —O—C₁₋₃alkyl, and (d) trifluoromethyl, and wherethe phenyl, heterocycle, and cycloalkyl are unsubstituted or substitutedwith 1-5 substituents where the substituents are independently selectedfrom: (a) halo, (b) trifluoromethyl, (c) hydroxy, (d) C₁₋₃alkyl, (e)—O—C₁₋₃alkyl, (f) —CO₂R⁹, (g) —CN, (h) —NR⁹R¹⁰, and (i) —CONR⁹R¹⁰ (j)NR⁹SO₂R¹⁰, (k) SO₂NR⁹R¹⁰ (l) phenyl, (m) heterocycle; and where thephenyl, heterocycle, and cycloalkyl may or may not be fused to anotherphenyl or heterocycle; R⁴ is selected from: (a) hydrogen, (b) hydroxy,(c) C₁₋₆alkyl, (d) C₁₋₆alkyl-hydroxy, (e) —O—C₁₋₃alkyl, (f) C₀₋₆CO₂R⁹,(g) —CONR⁹R¹⁰, and (h) —CN; or R³ and R⁴ may be joined together to forma ring which is selected from: (a) 1H-indene, (b) 2,3-dihydro-1H-indene,(c) 2,3-dihydro-benzofuran, (d) 1,3-dihydro-isobenzofuran, (e)2,3-dihydro-benzothiofuran, and (f) 1,3-dihydro-isobenzothiofuran, wherethe 1H-indene, 2,3-dihydro-1H-indene, 2,3-dihydro-benzofuran,1,3-dihydro-isobenzofuran, 2,3-dihydro-benzothiofuran, and1,3-dihydro-isobenzothiofuran may be unsubstituted or substituted with1-5 substituents where the substituents are independently selected from:(i) halo, (ii) trifluoromethyl, (iii) hydroxy, (iv) C₁₋₃alkyl, (v)—O—C₁₋₃alkyl, (vi) C₀₋₄CO₂R⁹, (vii) —CN, (viii) —NR⁹R¹⁰, and (ix)—CONR⁹R¹⁰ (x) NR⁹SO₂R¹⁰, (xi) SO₂NR⁹R¹⁰ (xii) phenyl, (xiii)heterocycle; R⁵, R⁶, R⁷ and R⁸ are independently selected from: (a)hydrogen, (b) hydroxy, (c) C₁₋₆alkyl, (d) C₁₋₆alkyl-hydroxy, (e)—O—C₁₋₃alkyl, (f) oxo, and (g) halo, (h) C₀₋₄CO₂R⁹, and (i) CF₃, orwhere R⁵ and R⁶, or R⁷ and R⁸ may be joined together via a C₂₋₃alkylchain to form a ring, or where R³ and R⁵, or R⁴ and R⁶ may be joinedtogether to form a ring which is phenyl, heterocycle, or cycloalkyl,wherein the ring is unsubstituted or substituted with 1-7 substituentswhere the substituents are independently selected from: (i) halo, (ii)trifluoromethyl, (iii) hydroxy, (iv) C₁₋₃alkyl, (v) —O—C₁₋₃alkyl, (vi)—CO₂R⁹, (vii) —CN, (viii) —NR⁹R¹⁰, (ix) —CONR⁹R¹⁰, and (x) phenyl; R¹¹is selected from: (a) hydrogen, (b) halo (c) C₁₋₆alkyl, (d) hydroxy, (e)CO₂R⁹, (f) —O—C₁₋₃-allyl, and (g) —NR⁹R¹⁰; R¹² is selected from: (a)hydrogen, (b) C₁₋₆alkyl, and (c) CO₂R⁹; n is an integer selected from 0,1, 2-and 3; and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.
 2. The compound of claim 1 of the formula Ib:

wherein the dashed line represents a single or a double bond and whereinR¹⁵ and R¹⁶ are independently selected from: (a) hydrogen, (b) halo, (c)trifluoromethyl, (d) hydroxy, (e) C₁₋₃alkyl, (f) —O—C₁₋₃alkyl, (g)—CO₂H, (h) —CO₂C₁₋₃alkyl, (i) —CN, and (j) heterocycle; andpharmaceutically acceptable salts and individual diastereomers thereof.3. The compound of claim 1 of the formula Ic:

and pharmaceutically acceptable salts and individual isomers thereof. 4.The compound of claim 1 of the formula Id:

where Z is a heterocycle selected from the group consisting of:benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl,indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl,pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof, and where the heterocycle may be unsubstituted orsubstituted with 1-3 substituents, where the substituents are selectedfrom: (a) hydrogen, (b) halo, (c) trifluoromethyl, (d) hydroxy, (e)C₁₋₃alkyl, (f) —O—C₁₋₃alkyl, (g) —CO₂H, (h) —CO₂C₁₋₃alkyl and (i) —CN,and where the heterocycle may be fused to a phenyl or anotherheterocycle, and pharmaceutically acceptable salts and individualdiastereomers thereof.
 5. The compound of claim 1 wherein X is —CONH—.6. The compound of claim 1 wherein R¹ is selected from:—C₀₋₆alkyl-phenyl, C₀₋₆alkyl-heterocycle, —C₁₋₆alkyl,—C₀₋₆alkyl-O—C₁₋₆alkyl-, —C₀₋₆alkyl-S—C₁₋₆alkyl-, and—(C₀₋₆alkyl)-(C₃₋₇cycloalkyl)-(C₀₋₆alkyl), where the phenyl,heterocycle, alkyl and the cycloalkyl are unsubstituted or substitutedwith 1-7 substituents where the substituents are independently selectedfrom: (a) halo, (b) hydroxy, (c) —O—C₁₋₃alkyl, (d) trifluoromethyl, (e)C₁₋₃alkyl, (f) —C₃₋₆cycloalkyl (g) —CO₂R⁹, wherein R⁹ is independentlyselected from: hydrogen, C₁₋₆ alkyl, C₅₋₆ cycloalkyl, benzyl or phenyl,which is unsubstituted or substituted with 1-3 substituents where thesubstituents are independently selected from: halo, C₁₋₃alkyl,C₁₋₃alkoxy and trifluoromethyl, (h) —CN, (i) —NR⁹R¹⁰, (o)—NR⁹COR¹⁰, (k)—NR⁹SO₂R¹⁰, (l) —NR⁹CO₂R¹⁰, (m) —NR⁹CONR⁹R¹⁰, (n) —CONR⁹R¹⁰, and (p)phenyl.
 7. The compound of claim 6 wherein R¹ is selected from: (1)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 substituentswhere the substituents are independently selected from: (a) halo, (b)hydroxy, (c) —O—C₁₋₃alkyl, (d) trifluoromethyl, (e) —CN, (f) —NR⁹SO₂R¹⁰,(g) —NR⁹CO₂R¹⁰, (h) —NR⁹CONR⁹R¹⁰, (i) heterocycle, (j) —CO₂R⁹, and (c)—CONR⁹R¹⁰, (2) —C₀₋₆alkyl-O—C₁₋₆alkyl-, which is unsubstituted orsubstituted with 1-6 substituents where the substituents areindependently selected from: (a) halo, and (b) trifluoromethyl, (3)—C₀₋₆alkyl-S—C₁₋₆alkyl-, which is unsubstituted or substituted with 1-6substituents where the substituents are independently selected from: (a)halo, and (b) trifluoromethyl, (4) —(C₃₋₅-cycloalkyl)-(C₀₋₆alkyl), whichis unsubstituted or substituted with 1-7 substituents where thesubstituents are independently selected from: (a) halo, (b) hydroxy, (c)—O—C₁₋₃alkyl, (d) trifluoromethyl, (e) —CN, (f) —NR⁹SO₂R¹⁰, (g)—NR⁹CO₂R¹⁰, (h) —NR⁹CONR₉R¹⁰, (i) heterocycle, (j) —CO₂R⁹, and (k)—CONR⁹R¹⁰, (5) phenyl, which is unsubstituted or substituted with 1-5substituents where the substituents are independently selected from: (a)halo, (b) hydroxy, (c) —O—C₁₋₃alkyl, (d) trifluoromethyl, (e) —CN, (f)—NR⁹SO₂R¹⁰, (g) —NR⁹CO₂R¹⁰, (h) —NR⁹CONR⁹R¹⁰, (i) heterocycle, (j)—CO₂R⁹, and (k) —CONR⁹R¹⁰, or where the phenyl may be fused to anotherphenyl or heterocycle, (6) heterocycle, which is unsubstituted orsubstituted with 1-5 substituents where the substituents areindependently selected from: (a) halo, (b) hydroxy, (c) —O—C₁₋₃alkyl,(d) trifluoromethyl, (e) —CN, (f) —NR⁹SO₂R¹⁰, (g) —NR⁹CO₂R¹⁰, (h)—NR⁹CONR⁹R¹⁰, (i) heterocycle, (j) —CO₂R⁹, and (k) —CONR⁹R¹⁰, or wherethe heterocycle may be fused to another heterocycle or a phenyl.
 8. Thecompound of claim 7 wherein that R¹ is selected from:

and positional and stereo isomers thereof.
 9. The compound of claim 1wherein R² is selected from: —(C₀₋₄alkyl)-phenyl and—(C₀₋₄-alkyl)-heterocycle, where heterocycle is selected from: furanyl,imidazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl,pyridazinyl, pyrimidyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, andtriazolyl, and N-oxides thereof, where the alkyl is unsubstituted orsubstituted with 1-7 substituents where the substituents areindependently selected from: (a) halo, (b) hydroxy, (c) —O—C₁₋₃alkyl,(d) trifluoromethyl, (e) —CO₂R⁹ and where the phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents where thesubstituents are independently selected from: (a) halo, (b)trifluoromethyl, (c) trifluoromethoxy, (d) hydroxy, (e) C₁₋₃alkyl, (f)—O—C₁₋₃alkyl, (g) —CO₂R⁹, (h) —S—C₁₋₃alkyl, (i) —SO₂—C₁₋₃alkyl, (j)—SCF₃, (k) —OPh, (l) —NR⁹R¹⁰, (m) —NR⁹—SO₂—R¹⁰, (n) —SO₂—NR⁹R¹⁰,(o)—CONR⁹R¹⁰, and (p) heterocycle.
 10. The compound of claim 9 whereinR² is selected from: —CH₂-phenyl and —CH₂-heterocycle, where theheterocycle is selected from: pyridyl, pyridazinyl, pyrimidyl, andN-oxides thereof, and where the phenyl or heterocycle is unsubstitutedor substituted with 1-3 substituents where the substituents areindependently selected from: (a) halo, (b) trifluoromethyl, (c)trifluoromethoxy, (d) hydroxy, (e) C₁₋₃alkyl, (f) —O—C₁₋₃alkyl, (g)—CO₂—C₁₋₃alkyl, (h) —CO₂H, (i) —S—C₁₋₃alkyl, (j) —SO₂—C₁₋₃alkyl, (k)—SCF₃, (l) —NH₂, (m) —NH—SO₂—C₁₋₃alkyl, (n) —SO₂—NH₂, and (o)heterocycle.
 11. The compound of claim 10 wherein R² is selected from:(1) —CH₂-(phenyl), (2) —CH₂-(4-bromophenyl), (3) —CH₂-(3-chlorophenyl),(4) —CH₂-(3,5-difluorophenyl), (5) —CH₂-((2-trifluoromethyl)phenyl), (6)—CH₂-((3-trifluoromethyl)phenyl), (7) —CH₂-((4-trifluoromethyl)phenyl),(8) —CH₂-((3-trifluoromethoxy)phenyl), (9)—CH₂-((3-trifluoromethylthio)phenyl), (10)—CH₂-((3-trifluoromethoxy-5-thiomethyl)phenyl), (11)—CH₂-((3-trifluoromethoxy-5-methoxy)phenyl), (12)—CH₂-((3-trifluoromethoxy-5-methanesulfonyl)phenyl), (13)—CH₂-((3-trifluoromethoxy-5-amino)phenyl), (14)—CH₂-((3-trifluoromethoxy-5-aminomethanesulfonyl)phenyl), (15)—CH₂-((3-trifluoromethoxy-5-sulfonylamino)phenyl), (16)—CH₂-((3,5-bis-trifluoromethyl)phenyl), (17)—CH₂-((3-fluoro-5-trifluoromethyl)phenyl), (18)—CH(CH₃)-((3,5-bis-trifluoromethyl)phenyl), (19)—C(CH₃)₂-((3,5-bis-trifluoromethyl)phenyl), (20)—CH₂-(4-(2-trifluoromethyl)pyridyl), (21)—CH₂-(5-(3-trifluoromethyl)pyridyl), (22)—CH₂-(5-(3-trifluoromethyl)pyridazinyl), (23)—CH₂-(4-(2-trifluoromethyl)pyridyl-N-oxide), and (24)—CH₂-(5-(3-trifluoromethyl)pyridyl-N-oxide).
 12. The compound of claim 1wherein R³ is phenyl or heterocycle, where the phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents where thesubstituents are independently selected from: (a) halo, (b)trifluoromethyl, (c) hydroxy, (d) C₁₋₃alkyl, (e) —O—C₁₋₃alkyl, (f)—CO₂R⁹, (g) —CN, (h) —NR⁹R¹⁰, and (i) —CONR⁹R¹⁰.
 13. The compound ofclaim 12 wherein R³ is phenyl or heterocycle, where the phenyl orheterocycle is unsubstituted or substituted with 1-3 substituents wherethe substituents are independently selected from: (a) halo, (c) hydroxy,(d) C₁₋₃alkyl, (e) —O—C₁₋₃alkyl, and (f) —CO₂R⁹.
 14. The compound ofclaim 13 wherein R³ is phenyl, para-fluorophenyl, 3-carboxyphenyl,3-pyridyl, 3,5-pyrimidyl, 1-benzimidazole, 3-indole, 1-indazole,1-pyrrole, imidazoyl, diazoyl, triazoyl or tetrazoyl.
 15. The compoundof claim 1 wherein R⁴ is selected from: (a) hydrogen, (b) hydroxy, (c)—CO₂C₁₋₆alkyl, (d) —CN, (e) fluoro, and (f) methyl.
 16. The compound ofclaim 1 wherein R⁵ and R⁶ are independently selected from: (a) hydrogen,(b) hydroxy, (c) —CH₃, (d) —O—CH₃, (e) oxo, and (f) -fluoro.
 17. Thecompound of claim 1 wherein R¹¹ is hydrogen.
 18. The compound of claim 1wherein R¹² is hydrogen.
 19. The compound of claim 1 of the formula:

wherein the dashed line represents a single or a double bond, R⁵ ishydrogen or methyl; and pharmaceutically acceptable salts and individualdiastereomers thereof.
 20. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts and individual diastereomersthereof.
 21. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts and individual diastereomersthereof.
 22. A compound which is selected from the group consisting ofthe title compounds of the Examples, and pharmaceutically acceptablesalts and individual diastereomers thereof.
 23. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1.24. A method for modulation of chemokine receptor activity in a mammalin need thereof which comprises the administration of an effectiveamount of the compound of claim
 1. 25. A method for treating,ameliorating or controlling an inflammatory or immunoregulatory disorderor disease which comprises administering to a patient in need thereof aneffective amount of the compound of claim
 1. 26. A method for reducingthe risk of an inflammatory or immunoregulatory disorder or diseasewhich comprises administering to a patient in need thereof an effectiveamount of the compound of claim
 1. 27. A method for treating,ameliorating or controlling rheumatoid arthritis which comprisesadministering to a patient in need thereof an effective amount of thecompound of claim 1.